1.
1. Differentiation well differentiation poor differentiation 2. Proliferation ()3. Invasion 4. Metastasis 1. Initiation (DNA mutation) 2. Promotion reversible stage
3. Conversion step 4. Tumor progression
** oncogene, DNA repair gene suppressor gene (angiogenesis)
TNM
T tumor size
N lymph node involvement
M metastasis
Induction Consolidation induction Intensification Maintenance Adjuvant chemotherapy neoadjuvant , primary chemotherapy palliative salvage regimen induction
(BSA ) BSA =
lab
lab 1. Platelet > 100, 000 /mm32. Hct 30%
3. WBC > 3000 /mm34. ANC > 1500
2. (cell cycle) 2 1 cell cycle (cell cycle phase specific anticancer)phaseanticancer
1. (preparation phase interphase) cell cycle1.1 G0 phase
2. 1.2 G1 phase gap1 phase DNAAsparagenase
1.3 S phase synthesis phase Antimetabolites, MTX, 5FU, Ara-C, 6MP, gemcitabine
1.4 G2 phase gap2 phase Bleomycin, podophyllotoxin, mitomycin C, etoposide
2 mitotic phase M phase nucleus cytoplasm 2 M 2 Go G1Antimitotics: vinka alkaloid vincristine, taxol paclitaxel
1. cell cycle phase specific: 3 1
2. non cell cycle phase specific: phase alkylating agents cyclophosphamide, ifosfamide, cisplatin, carboplatin
2
Antimetabolites:
Methotrexate (Antifolate)
dihydrofolate reductase (DHFR) inhibitor DNA S phase () - dose limiting toxicity: (mucositis) - : acute hepatitis
- : pneumonitis
*continuous infusion * bolus infusion ** Leucovorin (reduce folate) antidote MTX continuous infusion cell cycle
5-fluorouracil (5-FU)
Prodrug, Pyrimidines analogue
thymidylate synthase (TS) inhibitor DNA
5-FU FUMP FUDP FUTP RNA
dose limiting toxicity: mucositis ()
leucovarin FdUMP TS enzyme
Capecitabine
Prodrug 5-FU
5-FU
- dose limiting toxicity: hand foot syndrome ( vitamin B6 150 mg/day) mucositis, **hand foot syndrome 2-12 (dysesthesia) 2 hand foot syndrome 4
Cytarabine (Ara-C)
Pirimidine analog
DNA/RNA polymerase inhibitor ( DNA)dose limiting toxicity: () : , hepatitis, IT necrotizing leukoencephalopathy
gemcitabine
DNA polymerase inhibitor
ribonucleotide reductase inhibitordose limiting toxicity: ( )
Cyclophosphamide
Prodrug
phosphamide mustard DNA DNA dose limiting toxicity: () hemorrhagic cystitis ( acrolein cyclophosphamide) mesna (mesna acrolein )
ifosfamide
Prodrug
isophosphamide mustard DNA DNA dose limiting toxicity: () hemorrhagic cystitis ( acrolein ifosfamide) mesna (mesna acrolein )
Mitomycin-C
DNA alkylation cross linking
dose limiting toxicity: ( )
Streptomyces caespitosus
Hydroxyurea
Reboneucleotide reductase inhibitor S phasedose limiting toxicity:
Antimetabolites: platinum compounds:
Cisplatin
Platinum DNA platinum-DNA adduct intrastrand crosslink DNA ** RNA dose limiting toxicity: nephrotoxicity ototoxicity ( irreversible) peripheral neuropathy sensory neuropathy** cisplatin 50 mg/m2 NaCl 1-2 mannitol 12.5-25 cisplatin
carboplatin
platinum-DNA adduct intrastrand crosslink DNA ** RNA
dose limiting toxicity: () ototoxicity
peripheral sensory neuropathy
nephrotoxicity** carboplatin target AUC Scr ** D5W
oxaliplatin
platinum-DNA adduct intrastrand crosslink DNA ** RNA ** dose limiting toxicity: sensory neuropathy ()
ototoxicity
Antimicrotubules: Vinca Alkaloids
Vincristin, Vinblastin
Vincristine : R1 = CHO, Vinblastine R1 = CH3 polymerization depolymerization microtubule mitotic spindle chromosome cell death- Vincristine: dose limiting toxicity: peripheral neuropathy- Vinblastine Vinorelbine: dose limiting toxicity: neutropenia-** potent vesicant agent ()-
Antimicrotubules: Taxol
Paclitaxel
. Subunit tubulin polymerization tubulin depolymerization
- dose limiting toxicity: neutropenia
- : Hypersensitivity reaction cremorphore EL premedication dexamethasone
- Peripheral Neuropathy
- Dermatologic hand-foot syndrome
- Vesicant drug
Docetaxel
. Subunit tubulin polymerization tubulin depolymerization
- Fluid retention syndrome: premedication corticosteroid 3 doses 2. Dermatologic toxicity hand-foot syndrome : vitamin B6
- dose limiting toxicity: neutropenia
- Hypersensitivity reaction paclitaxel tween 80 Fluid retention syndrome SE docetaxel
Topoisomerase inhibitors: phase specific (G2 phase, S phase)
Irinothecan
Topoisomerase I break single strand DNA cell - dose limiting toxicity: Neutropenia
**diarrhea acute 24 hr cholinergic activity atropine late diarrhea 5-11 loperamide 4 mg stat then 2 mg q 2-4 hr 12 hrs
Etoposide
Topoisomerase II
DNA double strand DNA DNA
- dose-limiting toxicity : mucositis
- hypotension ()
Anthracycline:
Doxorubicin, Epirubicin, Idarubicin
Topoisomerase II
DNA double strand DNA DNA
- acute dose limiting toxicity: - chronic dose limiting toxicity: Cardiotoxicity (cumulative dose limiting cardiomyopathy; doxorubicin 550 mg/m2, epirubicin 900 mg/m2) **Dexrazoxane free radical scavenger free radical 3. Vesicant drugs: ** doxorubicin baseline EKG LVEF CHF ** cardiomyopathy LVEF 10 LVEF < 50% cumulative dose doxorubicin ~ 450 mg/m2 baseline LVEF < 50% **doxorubicin Streptomyces species **liposomal doxorubicin
Miscellaneous agents:
Bleomycin
DNA DNA free radical dose limiting toxicity: pnuemocititis ()
Hydroxyurea
Reboneucleotide reductase inhibitor S phasedose limiting toxicity:
Selective estrogen receptor modulators (SERMs):
Tamoxifen
receptor estrogen antiestrogenic estrogen
SE: hot flush (menopause symptom), hypercalcemia, endometrial cancer uterine sarcoma** pre-menopause
Selective estrogen receptor downregulators (SERDs):
Fulvestrant
estrogen receptor drug-ER complex
Aromatase inhibitors:
Nonsteroidal compound: anastrozol, letrozol Steroidal compound: exemestane
aromatase testoseterone estradiol Reversible inhibitionSE: arthritis, arthralgia, cardiovascular events, decrease bone density ( bisphosphonate )**** post-menopause
Side Effects 1. Nausea/Vomiting
3
Emetic Risk
I.VOral
High risk- AC combination (doxo/epirubicin cyclophosphamide )
- Cyclophosphamide > 1500 mg/m2- Cisplatin > 50 mg/m2Day 1 : 5-HT3 RA + Dexamethasone + Apprepitant (Ondansetron 8 mg)
Day 2-3 : Dexamethasone + Apprepitant (Dexa 20 mg Aprepitant 12 mg)
Moderate risk (30-90%)- Cytarabine > 1 g/m2- Cyclophosphamide < 1500 mg/m2- Idarubucin, Ifosfamide
- Methotrexate 250 1000 mg/m2- Cisplatin < 50 mg/m2
- Carboplatin, Doxorubicin
- Epirubicin, Oxaliplatin > 75 mg/m2, Irinothecan
Cyclophosphamide
Etoposide
VinorelbineDay 1 : 5-HT3 RA + Dexamethasone (Dexa 12 mg Aprepitant)
Day 2-3 : 5-HT3 RA Dexamethasone Aprepitant AC combine cisplatin,irinothecan,MTX
Low risk (10-30%)- Docetaxel, Paclitaxel, 5-FU, Etoposide
- Gemcitabine, Methotrexate 50 250 mg/m2CapecitabineDay 1: Dexamethasone Prochlorperazine Metoclopamide Diphenhydramine
Minimal risk ( Docetaxel,
b. Secondary prophylaxis Primary prophylaxis
- G-CSF supportive therapy dose-dense regimen
3.Anemia
erythropoietin 4 NCI
Scales
None : 14 18 g/dL : 12 16 g/dL
Mild10 g/dL normal range
Moderate8-10 g/dL
Severe6.5 7.9 g/dL
Life-threatening< 6.5 g/dL
1. Asymptomatic
2. Symptomatic - oral parenteral
- parenteral premed diphenhydramine para test dose hypersensitivity reaction
Erythropoietic agent
Epoetin-alfa 150 U/kg sc TIW 300 U/kg sc TIW
Darbepoetin 3 mcgkg q 2 wk 5 mcg/kg sc 2 wk - 4 (Epoetin-alfa) 6 (Darbepoetin)hemoglobin 1 g/dL
4.Hypercalcemia
(Bone matastasis)
: GFR calcium excretion
: NSS Loop diuretic Bisphosphonate cancer pamidronate(1st line) i.v drip, zoledronic acid (1st line )
Corticosteroids prednisolone
2. Neurologic complication
Peripheral neuropathy tingling paresthesia,loss of angle jerk reflex - Platinum compound Cisplatin,Oxaliplatin ()- Methotrexate
- Taxanes
- 5-FU
- Vinca alkaloid
- Cytarabine
:
- Calcium gluconate 1 g + MgCl2 1 g - Gabapentin 200 300 mg
:
- Calcium gluconate 1 g + MgCl2 1 g 3. Cardiotoxicity
cardiomyopathy Anthracycline- Dexarazone cardioprotectant - Doxorubicin liposomal -5-FU cardiomyopathy continuous bolus
- Taxanes 4. Extravasation
Vesicant tissue necrosis Anthracyclines
Antibiotics antitumors
Vinca alkaloids
Taxanes
Cisplatin > 0.5 mg/ml
Irritant necrosis
Alkylating Ifosfamide,Carmustine
Platinum
Topoisomerase II inhibitor
:
scar, vein NSS flush 2-3 Doxorubicin, Taxanes
Vinca alkaloid , Etoposide
antidotes
5 antidote extravasation
DrugsAntidote
AnthracyclineDMSO
Dexarazone ( DMSO)
MitomycinDMSO
Vinca alkaloidsHyaluronidase
Taxanes, EtoposideHyaluronidase
5. Dermatologic complication Taxanes
5-FU
Capecitabine
Hand-foot syndrome,onychomadesis ( Capecitabine 5-FU )
: , , - Pyridoxine
6. Diarrhea and Mucositis
Mucositis - Antimetabolites (5-FU , Methotrexate )
- Vinca alkaloids
- Anthracyclines
:
- Cryotherapy : 30
- Ranitidine Omeprazole Cyclophosphamide, Methotrexate,5-FU
- palifermin
:
Diarrhea Vincristine, Irinothecan : Loperamide
7. Nephrotoxicity
- Platinum compounds: cisplatin : , mannitol furosemide, KCl MgSO4- Cyclophosphamid Methotrexate
: 49
4 50 Non-Small Cell Lung Cancer (NSCLC) Satge IV
Cisplatin 100 mg/m2 IV drop over 1 hour on day 1
Etoposide 100 mg/m2 IV drip over 1 hour on day 1,2
60 kg. 180 cm Surface area= 1.73 m2 1. Cisplatin a. 150
b. 175
c. 200
d. 225
e. 250
2. Acute Emetic
a. Ondansetron
b. Dexamethasone
c. Metoclopramide
d. Ondansetron + Dexamethasone
e. Metoclopramide + Dexamethasone
3. Cisplatin a. Akylating agent
b. Topoisomerase II inhibitor
c. Antimetabolite
d. Intercalating agent
e. Inhibitor of mitosis
4. Cisplatin (Nephrotoxicity) a. b. Magnesium
c. Osmotic diuretic Mannitol
d. Cisplatin Sodium chloride
5. etoposide stability
: At temperature in D5W or NS in polyvinyl
0.2 mg/ml : 96 hours
0.4 - 0.21 mg/ml : 48 hours
0.6 - 0.41 mg/ml : 8 hours
1.0 - 0.61 mg/ml : 2 hours
manufacturer does not recommended administration at conc. more than 0.4 mg/ml due to highly unpredictable time to precipitation
etoposide (100 mg/m2) D5W 500 ml a. 96 .b. 48 .c. 8 .d. 2 . 50
Case Cancer
Pt. CHOP regimen , . pt. s/e 49
9
+ Lab + +BSA 1. BSA
2. BSA
1. cisplatin
1. coordinate platinum anticancer drug
2. oral parenteral
3. Cis trans isomer 4. 5. 2. 1. alkylating agents DNA 2. folic acid antagonist nucleic acid
3. purine antagonist nucleic acid
4. pyrimidine antagonist nucleic acid
5. DNA 3. drug interaction 1. Tamoxifen-warfarin
2. Mercaptopurine-allopurinal
3. Cisplatin-cimetidine
4. Methotrexate-phenobarbital
5. Doxorubicin-tetracycline4. ondansetron 1. 30 2. 4 3. antiemetic potent 72 4. 5.
5. 1. antiproliferative agent
2. 3. 4. 5.
6. cyclophosphamide 1. Nausea/vomiting
2. Dermatitis
3. Hemorrhagic cystitis
4. Alopecia
5. agranulocytosis7. Vincristin1. Alkylating agents
2. Vitamin D derivative
3. Antimetabolites
4. Alkaloid 5. hormone8. leucovarin methotrexate 1. uptake MTX 2. MTX 3. MTX 4. MTX
9. 1. Carmustine2. Darcarbazine
3. Doxorubicin
4. 5-fluorouracil
5. vincristine
Recommended