آياته من النفس في ما عيناكا ولعل ترى لو عجاب عجبإذا بأسرار مشحون أعياكا والكون لها تفسيرا حاولت

الردى يد تخطفته للطبيب أرداكا قل من األمراض ياشافيعافاكا من الطب فنون عجزت ما بعد وعوفي نجا للمريض قل

علة من ال يموت للصحيح دهاكا قل ياصحيح بالمنايا منسوداني ) ( بديوي علي إبراهيم للشاعر

ChemotherapyInduced

Cardotoxicity

By Salah Mabrouk

Assisstant lecturer of

Medical OncologySECI Assiut University

Definition of cardotoxicity Chemotherapy induced cardotoxicity

ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment

Radiotherapy induced cardotoxicity

Definition of cardiac toxicity

Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure

Anthracyclines

Epidemiology

bullFirst recognized Mid to late 1970rsquos

bullIncidence 18-65

bullMortality gt20

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

ChemotherapyInduced

Cardotoxicity

By Salah Mabrouk

Assisstant lecturer of

Medical OncologySECI Assiut University

Definition of cardotoxicity Chemotherapy induced cardotoxicity

ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment

Radiotherapy induced cardotoxicity

Definition of cardiac toxicity

Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure

Anthracyclines

Epidemiology

bullFirst recognized Mid to late 1970rsquos

bullIncidence 18-65

bullMortality gt20

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Definition of cardotoxicity Chemotherapy induced cardotoxicity

ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment

Radiotherapy induced cardotoxicity

Definition of cardiac toxicity

Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure

Anthracyclines

Epidemiology

bullFirst recognized Mid to late 1970rsquos

bullIncidence 18-65

bullMortality gt20

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Definition of cardiac toxicity

Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure

Anthracyclines

Epidemiology

bullFirst recognized Mid to late 1970rsquos

bullIncidence 18-65

bullMortality gt20

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Anthracyclines

Epidemiology

bullFirst recognized Mid to late 1970rsquos

bullIncidence 18-65

bullMortality gt20

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Anthracyclines

The most well-known is doxorubicin )Adriamycinreg(

Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Pathogenesis

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative

metabolism4 Anthracycline affinity for cardiolipin results in drug

accumulation5 Genetic polymorphisms in NAD(P)H oxidase and

Doxorubicin efflux transporters

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

I- Free radical formation A- Enzymatic reaction in mitochondria

Quinone

Aminoresidue

Sugar residue

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

I- Free radical formation Enzymatic reaction in mitochondria

Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases

This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle

This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH

superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper

will be converted to the very reactive oxidizing species hydroxyl radical )HO(

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

I- Free radical formation B- Non-enzymatic reaction with Iron

Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell

These complexes are apt to generate ROS in the presence or the absence of reducing components

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and

nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS

ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of

antioxidant enzymes Mitochondria are particularly susceptible to free radical damage

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Cytochrome C release apoptotic signal

Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1

TNFFAS-R tumor necrosis factorFas receptor

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors

(hypertension diabetes increasing total cholesterol Obesity and Smoking)

Gender female sex

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small

dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Induction Treatment Of AMLInduction Treatment Of AML

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

bullADR amp DNR - 450 mgm2 if CPA is also given

- 550 mgm2 if not

bullIdarubicin 75 mgm2

bullMitoxantrone 140 mgm2

Cumulative doses of anthracyclines

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than

doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)

However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold

van Dalenet al Cochrane Database Syst Rev (2006)

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Treatment related risk factors

2- Dosing schedule

bull Single large dose gt smaller frequent dosing

bull The dose every 3 weeks gt weekly doses

bull Bolus injection (peak levels) gt continuous infusion

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications

(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728

Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Patient related risk factors

2- Preexisting cardiovascular disease or cardiac risk factors

Hypertension

Diabetes

increasing total cholesterol)

Obesity

Smoking

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Patient related risk factors 3- Gender female sex

Controversy

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Clinical manifestation stages

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Type I and Type II Treatment-Related Cardiotoxicity

Type Indash Cumulative-dose related

ndash Irreversible (cell death)

ndash Typical biopsy changes

ndash Doxorubicin is the model

Type IIndash Not cumulative-dose related

ndash Largely reversible (cell dysfunction)

ndash Absence of anthracycline-like biopsy changes

ndash Trastuzumab is the model

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias

Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)

Chronic cardiotoxicity Contractile dysfunction Heart failure

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a

single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and

hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration

The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes

1 Toxic pericarditis 2 Toxic Myocarditis

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Chronic Cardiotoxicity Include

1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)

2 Heart failure This is the most severe form of doxorubicin

cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively

with increasing doses

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T

bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Echocardiography Benefits Provides a wide spectrum of information on cardiac

morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and

diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac

disease Both FS( fractional shortening ) and LVEF are affected by

preload and afterload

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Echocardiography

Nousiainen Eur J Haematol 62135-141 1999

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the

myocardium2 B-type natriuretic peptide (BNP) cardiac hormone

Benefits Troponin is a highly specific and sensitive biomarker

for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the

development of future ventricular dysfunction as well as its severity

Limitation Data regarding clinical value are limited

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Magnetic resonance imaging

Benefit Valuable tool to assess myocardial function and

damage

Limitations High costs of repeated examinations Limited availability

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Computed tomography

Benefits Image quality similar to magnetic resonance

imaging with Lower cost

Limitations High radiation dose Limited availability

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Scintigraphy

Benefit Sensitive method to detect myocyte damage

in patients after doxorubicin therapy

Limitation Larger prospective trials required to ascertain

potential role

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Multiple uptake gated acquisition scan (MUGA scan)

Benefits Well-established and well-validated method to

determine ejection fraction Can also assess regional wall motion and diastolic

function (nonstandard)

Limitations No information on valve function LVEF measurements are not sensitive for the early

detection of preclinical cardiac disease

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Endomyocardial biopsy

bull Microscope Changes1ndash Mitochondrial defects

2ndash Diminished cardiac myocyte calcium handling properties

3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Endomyocardial biopsy

Benefits Provides histological evidence of cardiotoxicity

Limitations Invasive Small sample of myocardium tested

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Prevention

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Prevention1 Screening for risk factors and prevention of cardiac

events

2 Dose limitation(lt 550mg m2 )

3 Dosing Schedules modification

4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)

5 Use agents to prevent the cardiotoxicity

6 Use cardioprotective agent (Dexrazoxane)

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Screening for risk factors and prevention of cardiac events

Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment

1 le 30rarrDonrsquot give anthracyclines

2 30ndash50rarr give with monitoring of LVEF

3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose

bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Dose limitation keep the total lifetime cumulative dose below

the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative

doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Dosing Schedules It should be as possible in

bull Smaller frequent dosing

bull Weekly doses

bull Continuous infusion controversy

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Liposomal preparations of athracyclines

Figure Liposomes ndash

)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer

)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised

tumour vasculature

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated

NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or

bioconjugation

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin

(Doxilreg or Caelyx reg)

Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Liposomal preparations of athracyclines

(Caelyxreg) Liposomes are preferentially taken

up by tissues enriched in phagocytic reticuloendothelial cells

In many trials it appears to be as effective as standard doxorubicin

Side effects

mucositis and palmoplantar erythrodysesthesia

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Cardioprotective agent (Dexrazoxane= Cardioxanereg)

Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron

which leads to reactive oxygen production It has been tested in multiple clinical trials and has

been shown to reduce cardiac toxicity The recommended dosage ratio of

dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Dexrazoxane

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

7

10

54

1

15

12

4

15

20

0 5 10 15 20 25

Doxo 500 mgm2

Doxo 1000 mgm2

Doxo bolus gt 550 mgm2

Doxo low dose weekly gt 600 mgm2

Doxo (400-499 mgm2) + Dexrazoxane

Dauno 500 mgm2

Dauno 1000 mgm2

Epirubicin lt 900 mgm2

Epirubicin 1000 mgm2

Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with

Dexrazoxane

CHF ()

Hensley ML et al J Clin Oncol 1999 17(10)3333-3355

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

ASCO Recommendations

Not recommended for initial therapy Breast patients receiving more than 300

mgm2 of doxorubicin Consideration in patients with other

malignancies receiving more than 300 mgm2 of doxorubicin

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Dexrazoxane and response to chemotherapy

Some data suggests that dexrazoxane may decrease response to chemotherapy

One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group

There has been no difference in overall survival or progression free survival in this trial

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

New prevention strategies In addition to new biomarkers for risk stratification

there are new potential approaches to prevention of anthracycline cardiotoxicity

These include

1 Angiotensin-converting enzyme (ACE) inhibitors

2 Angiotensin II receptor blockers (ARBs)

3 Carvedilol

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress

ACE inhibitors

Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Angiotensin receptor blockers ARBs have been found to have intrinsic

antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan

significantly reduced changes in the left ventricular end-diastolic diameter

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy

Jensen et al Annals of Oncology 2002 13499-709

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Carvedilol Carvedilol blocks beta1 beta2 and alpha1

adrenoceptors and has potent antioxidant and anti-apoptetic properties

Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity

Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting

Further large randomised trials are needed

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Non-anthracycline

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE

Cyclophosphamideifosfamide Myocarditis CHF 2517

Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia

05

Fluorouracil MI angina hypotension coronary vasospasm 16ndash68

Rituximab Hypotension hypertension arrhythmia 25

Arsenic trioxide QT prolongation tachycardia 8ndash55

Trastuzumab CHF 7ndash28

Thalidomide Pulmonary hypertension Unknown

Etoposide MI hypotension 1ndash2

Vinca alkaloids MI autonomic cardioneuropathy 25

Pentostatin MI CHF acute arrhythmia 3ndash10

Cytarabine Arrhythmia pericarditis CHF Unknown

Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease

Unknown

Busulfan Endocardial fibrosis Unknown

Cisplatin Acute MI Unknown

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset

ndash in the first 72 hours of the initial treatment cycle

Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease

Pathogenesisndash coronary spasm

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

5-FLUOROURACIL )5-FU(

Characteristics

bull The second most common bull Not dose related

bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction

bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in

patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and

nitrates remains unclear Most patients respond to conservative antianginal

therapy and supportive care

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

CYCLOPHOSPHAMIDE Incidence

bull 25bull The life-threatening incidence is 5 to 10 of patients

Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity

Risk factors ndash High dose regimens carry greater risk ie after the use of

very high does (120-140mgkg) in preparation for bone marrow transplant

ndash Prior treatment with anthracycline or mediastinal irradiation

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade

NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left

ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)

Close clinical monitoring of patients for signs and symptoms of congestive heart failure

If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF

These patients should be treated symptomatically for congestive heart failure

Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Vinca alkaloids bleomycin and cisplatin Pathogenesis

ndash Vasospasm in addition to electrolyte wasting with cisplatin

Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids

ndash Raynaud phenomenon

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Taxanes Incidence 05 Pathogenesis

ndash It may be related to the cremaphor vehicle in paclitaxel

Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction

Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Taxanes Prevention and management No risk factors however patients with underlying

cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention

neither be stopped nor the dose reduced in these patients

Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or

increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity

Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Cardiotoxicity Associated With Biologic

Agents

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Trastuzumab Incidence

bull 2 risk of developing cardiac dysfunction if used alone

bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Trastuzumab )Herceptinreg(

bull Risk factors for the cardiomyopathy

1048766 If given with doxorubicin

1048766 If prior chest radiation therapy

1048766 If diabetes

1048766 If history heart valve disease

1048766 If history heart artery disease

bull In other words risk if prior heart disease

bull Not dose related

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Copyright copy2008 American Association for Cancer Research

Bird B RJ H et al Clin Cancer Res 20081414-24

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Type I (myocardial damage) Doxorubicin

May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress

Cumulative dose related

Free radical formation oxidative stressdamage

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death

High

Type II (myocardial dysfunction) Trastuzumab

High likelihood of recovery

Not dose related

Blocked ErbB2 signaling

Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion

Increasing evidence for the relative safety of rechallenge additional data needed

Low

Type Agent

Response to

Therapy

Dose

Mechanism

Cardiac testing

Effect of Rechallenge

Effect of late sequential

stress

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

RITUXIMAB Incidence 25 Include

ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation

and cardiogenic shock Most of these reactions (80) occur during the

first infusion and may be associated with a cytokine-release phenomenon

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

RITUXIMAB

Prevention and management Discontinued in patients who develop significant

arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is

warranted especially in patients with pre-existing cardiac disease

It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Sunitinib

Sunitinib caused mitochondrial injuryRelease of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Imatinib Cardiac death myocardial infarction and

congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Imatinib

Release of cytochrome C

Caspase activation ATP depletion

Apoptosis Necrosis

Myocyte lossLV

dysfunction

ER stress response JNK

BAX activation

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-

dependent manner Rare

ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Dasatinib

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib

arrhythmia and palpitations Severe pericardial effusions

QT prolongation

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Bevacizumab)Avastinreg(

Heart Attacks and Chemotherapy

bull May occur with bevacizumab (Avastinreg)

1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth

Avastin can cause heart attacks angina CHF high blood pressure strokes and clots

Risk is 2 especially if prior heart disease

Risk is 14 if given together with doxorubicin

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Bevacizumab )Avastinreg(

bull Heart toxicity can manifest as

1048766 Decreased muscle function (EF)

1048766 Congestive heart failure

1048766 Rhythm problems

1048766 High blood levels of heart enzymes such as troponin T and troponin I

1048766 High blood levels of heart hormones such as BNP

1048766 Inflammation of the pericardium

1048766 Inflammation of the heart muscle

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in

various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and

potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually

acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients

to the cardiotoxic effects of arsenic trioxide

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Prevention and management A baseline ECG should be done before starting therapy to

assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction

and biweekly during consolidation If the QT interval is gt 500 ms the patient should be

evaluated for potential risk versus benefit with further therapy

Prior to each infusion electrolytes should be checked and corrected if low

Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively

Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes

Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

THALIDOMIDE Thalidomide is an immunomodulatory agent currently

used in the treatment of multiple myeloma and other malignancies

It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide

Both symptoms and pulmonary pressure resolved after cessation of thalidomide

The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

THALIDOMIDE Prevention and management High-resolution computed tomography (CT)

and D-dimer should be performed to rule out pulmonary embolism

Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure

Further therapy with thalidomide should be stopped as this is a reversible phenomenon

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

MITOXANTRONE

Transient arrhythmias (7)

Cardiac ischemia (5)

Edema (10)

Hypertension (4) E

Congestive heart failure cardiomyopathy (26)

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

MITOXANTRONE

The recommended maximum cumulative dose of mitoxantrone is 140 mgm2

The cumulative dose is lower with prior anthracycline therapy

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Other drugs

Busulfan (Myleran)

Cardiac tamponade or endomyocardial fibrosis

Bleomycin

Pulmonary fibrosis

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Radiation Therapybull Factors that increase the risk of heart damage

1 1048766 Extent of the coronary arteries in the field

2 1048766 Total radiation dose

3 1048766 Radation dose per fraction

4 1048766 Anterior fields versus tangential fields

5 1048766 Patient age especially under 20 years

6 1048766 Concomitant doxorubicin

7 1048766 Usual heart risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Radiation Therapy

bull Coronary artery disease

1048766 Increased risk if combined with doxorubicin

bull Pericarditis acute or chronic

bull Pericarditis and myocarditis

bull Cardiomyopathy

bull Diastolic dysfunction

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors

Radiation Therapy Recommendations for Radiation Therapy

bull Use cardiac blocking during therapy

bull Limit the concomitant use of doxorubicin (although it can be used before or after)

bull Minimize all other atherosclerotic risk factors