Standard care for breast cancer medical therapy

Early Breast CancerEarly Breast Cancer“Standard Care”“Standard Care”

Dr. Shad Salim AkhtarDr. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP(Edin)MBBS, MD, MRCP(UK), FRCP(Edin)Member Association of Fellows UICCMember Association of Fellows UICC

Consultant Medical OncologistConsultant Medical OncologistMedical DirectorMedical DirectorKing Fahd Specialist Hospital &King Fahd Specialist Hospital &Prince Faisal Oncology CenterPrince Faisal Oncology CenterBuraidah, Al-Qassim, KSABuraidah, Al-Qassim, KSA

عنها الله رضي عائشة النبي )} عن أنالله : إن قال وسلم عليه الله صلى

يتقنه .{( أن ً عمال أحدكم عمل إذا يحبNarrated Hadhrate Aisha (RAA)

The Prophet (SAW) said, “Indeed Allah loves among you the one who does the work (what ever he does) in the best way”

Breast Cancer ManagementBreast Cancer Management

DiagnosisDiagnosis– Clinical diagnosisClinical diagnosis– HistopathologyHistopathology

SurgerySurgery RadiotherapyRadiotherapy Systemic medical therapySystemic medical therapy

SurgeryLump Diagnostic Evaluation

Clinical examinationMammography

FNAUltrasound

Triple Assessment

Biochemical markers are essentialBiochemical markers are essential Chest X-ray RoutineChest X-ray Routine LUS/BS only if biochemical LUS/BS only if biochemical

abnormalities?abnormalities? CT scan/MRI/PETCT scan/MRI/PET

Breast Cancer-Preoperative StagingBreast Cancer-Preoperative Staging

Breast Cancer-Standard SurgeryBreast Cancer-Standard Surgery

NCI Consensus StatementNCI Consensus Statement

Complete excision of breast cancer with Complete excision of breast cancer with negative marginsnegative margins

Level I/II axillary lymph node dissectionLevel I/II axillary lymph node dissection

Jardines L et al: Breast Cancer in Cancer Management: PPR 2002; 173-

BCT-Need for RTBCT-Need for RT

InterventionIntervention Local FailureLocal Failure%%

BCT+AxD+RTBCT+AxD+RT 6-136-13

BCT+AxDBCT+AxD 18-3618-36

Local Failure rate at 10 years follow up

Percent reduction in local rec with RT 56-75%

Post mastectomy RadiotherapyPost mastectomy RadiotherapyCurrent ConsensusCurrent Consensus

Incomplete resection (micro/macro)Incomplete resection (micro/macro) >=4 positive nodes>=4 positive nodes T3 N+ tumorsT3 N+ tumors T3 GII/III & or Vascular InvasionT3 GII/III & or Vascular Invasion Diffusely growing tumors in >1 quadrantDiffusely growing tumors in >1 quadrant In T1 node positive (<3) trials neededIn T1 node positive (<3) trials needed Benefit should be maximum when no Benefit should be maximum when no

occult disease is presentoccult disease is presentOvergaard M: Eur J Cancer 2001; 37 (s7):33

Post mastectomy Post mastectomy Axillary RadiotherapyAxillary Radiotherapy

>= 4 nodes in level II>= 4 nodes in level II 50% removed nodes positive50% removed nodes positive Palpable metastatic lymph node >2 cmsPalpable metastatic lymph node >2 cms Margin of surgery <5mmMargin of surgery <5mm Extra nodal spread Extra nodal spread Axillary recurrence rate lower than chest wallAxillary recurrence rate lower than chest wall

Bartelink H: Ann Oncol 2000; 11(3):7

Post mastectomy RadiotherapyPost mastectomy RadiotherapyWhat is the optimal timing?What is the optimal timing?

Interval between Surgery & RT effects LRInterval between Surgery & RT effects LR Retrospective studies suggest max 6 wks Retrospective studies suggest max 6 wks

gapgap

Batelink H Ann Oncol 2000: 11 (s3):7

Post mastectomy RadiotherapyPost mastectomy RadiotherapyWhat is the optimal timing?What is the optimal timing?

CT vs RT timing?CT vs RT timing? Joint Center for Radiation StudyJoint Center for Radiation Study

– CT before RT betterCT before RT better– Distant failure lessDistant failure less– OS betterOS better– Benefit in node positive patients onlyBenefit in node positive patients only

Sandwich approachSandwich approach– Danish studyDanish study– British Columbia studyBritish Columbia study

Overgaard M: Eur J Cancer 2001; 37 (7):33

Breast Cancer-TreatmentBreast Cancer-Treatment

Halsted hypothesisHalsted hypothesis– Local control improves survivalLocal control improves survival

Systemic hypothesisSystemic hypothesis– Local control has no impact on survivalLocal control has no impact on survival

Present UnderstandingPresent Understanding– Maximal disease controlMaximal disease control

LocoregionalLocoregional SystemicSystemic

Adjuvant Medical TherapyAdjuvant Medical Therapy

EndocrineEndocrine ChemotherapyChemotherapy OthersOthers Who shall get itWho shall get it How long shall it be givenHow long shall it be given What type What type What doseWhat dose

TamoxifenTamoxifen

Should be used in all ER +ve pts regardless Should be used in all ER +ve pts regardless of:of:– AgeAge– Menopausal statusMenopausal status– Axillary node involvementAxillary node involvement– Tumor sizeTumor size

NIH and St Gallen Consensus Conferences

Tamoxifen How Long?Tamoxifen How Long?

TrialTrial DesignDesign StatusStatus TargetTarget ResultResultNSABP NSABP B-14B-14

5yrs vs 5yrs vs ContdContd

ReportedReported 11721172 Equivalence for OSEquivalence for OSLong use more End CaLong use more End Ca

ECOGECOGE4181E4181

5 yrs vs 5 yrs vs ContdContd

ReportedReported Equivalence for RFSEquivalence for RFS

ScottishScottish 5 yrs vs 5 yrs vs ContdContd

ReportedReported 342342 Equivalence for RFSEquivalence for RFSLong use more End CaLong use more End Ca

ATLASATLAS 5 yrs vs 10 5 yrs vs 10 yrs in ER+yrs in ER+

OpenOpen 2000020000 N/AN/A

ATTOMATTOM 5yrs vs 10 5yrs vs 10 yrs ER +?yrs ER +?

OpenOpen ?? N/AN/A

Lohrisch C et al: Eur J Cancer 2001; 37 (s7):45

Tamoxifen When?Tamoxifen When?

Sequential better ?Sequential better ? Data from ECOG trialData from ECOG trial

– PremenopausalPremenopausal– Node positiveNode positive– ER positiveER positive– CAF vs CAF+OA vs CAF+OA+TAMCAF vs CAF+OA vs CAF+OA+TAM– Last combination superiorLast combination superior

Davidson N et al: Proc Am Soc Oncol 1999; 18:67a (abstract 249)

Intergroup 0100 trialIntergroup 0100 trial CAFT+TCAFT+T CAF+TCAF+T Postmenopausal ptsPostmenopausal pts Node +Node + HR +HR + 8 yrs follow up8 yrs follow up



RegimenDFSCAFT+T62%CAF+T 67%

Albian KS et al: Proc ASCO:2002.

Sequential tamoxifen better

Adjuvant Medical TherapyAdjuvant Medical TherapyOxford Overview 2000-Ovarian AblationOxford Overview 2000-Ovarian Ablation

In the absence of CT Ovarian Ablation in In the absence of CT Ovarian Ablation in <50 yrs of age<50 yrs of age– Reduces Br Ca Rec-8.5%Reduces Br Ca Rec-8.5%– Improves survival-9.8%Improves survival-9.8%

OA + CT no such benefitOA + CT no such benefit Specific focus on HR+ premenopausal pts Specific focus on HR+ premenopausal pts

not availablenot available

Ovarian AblationOvarian Ablation OA+/- Tam vs CT OA+/- Tam vs CT 8 randomized trials8 randomized trials Conclusion: OA+/- Tam=CMFx6Conclusion: OA+/- Tam=CMFx6 To note:To note:

– CMF not anthracyclines were triedCMF not anthracyclines were tried– Tam was not used wth CMFTam was not used wth CMF

May be used as an alternative to CT in ER May be used as an alternative to CT in ER rich ptsrich pts– Definite premenopausalDefinite premenopausal– Tam must be addedTam must be added

Davidson N ASCO 2002 Education Book; 156

Tamoxifen+Ovarian AblationTamoxifen+Ovarian Ablation

No dataNo data Trials are onTrials are on

ATAC TrialATAC TrialAnastrozolAnastrozolee

TamoxifenTamoxifen Comb(%Comb(%))

Total(%)Total(%)

Ist Ist eventevent

31253125 31163116 31253125 93669366

LRLR 6767 8383 8181 231231DRDR 158158 182182 204204 544544Contral Contral CaCa

1414 3333 2828 7575

Deaths Deaths before Rbefore R

7878 8181 7070 229229

TotalTotal 317317((10.1%)10.1%) 379379((12.2%)12.2%) 383383((12.312.3)) 10791079((11.5)11.5)ATAC Trialists Group: Lancet 2002; 359:2131

Shall we stop using TamoxifenShall we stop using Tamoxifen

NONO Single trialSingle trial Short follow upShort follow up Safety for 5 yrs?Safety for 5 yrs? Additive effect over years?Additive effect over years? Carry over effect?Carry over effect?

When to use Anastrozole?When to use Anastrozole?

As adjuvant in As adjuvant in – Postmenopausal ptPostmenopausal pt– HR +ve tumourHR +ve tumour

May be considered in pts with Tam May be considered in pts with Tam contraindicationcontraindication

NO IndicationNO Indication– To switch from Tam to AnastrozoleTo switch from Tam to Anastrozole– To add after 5 yrs of TamTo add after 5 yrs of Tam– Other AI equivalent?Other AI equivalent?

Risk of Recurrence Node negativeRisk of Recurrence Node negative

Risk level Rec at 10yrsLow Risk <10 %High Risk ~20 %Intermediate Risk 10-20%

EBCTG: Lancet 1992; 339:1

Risk of Recurrence Node PositiveRisk of Recurrence Node Positive

Risk level 10 yr surv1-3 nodes 40-60 %>=4 nodes 25%


Absolute reduction in mortality – Absolute reduction in mortality – effect of medical therapyeffect of medical therapy

10 yr risk of death Abs benefit in 100 women from breast cancer if therapy reduces ann (%)

odds of death by

10-20 4 220-40 8 440-80 12 6


30% <15 %

Adjuvant Medical Therapy 2000 Oxford Overview Adjuvant Medical Therapy 2000 Oxford Overview 3-6 months Chemotherapy3-6 months Chemotherapy

Pre -ve 7%Pre +ve11%Post -ve 2%Post +ve 3%

2000 Review unpublished data

Menop Node Imp in Surv

Regardless of tamoxifen usage

Chemotherapy in Premenopausal PtsChemotherapy in Premenopausal Pts

Regardless of HR statusRegardless of HR status All node positive patientsAll node positive patients Node negative with non low risk statusNode negative with non low risk status In very low risk HR-ve otherwise good In very low risk HR-ve otherwise good

prognosis role unknown, most would use itprognosis role unknown, most would use it In very low risk node-ve disease uncertainIn very low risk node-ve disease uncertain


Chemotherapy in Postmenopausal Chemotherapy in Postmenopausal PtsPts

50-69 yrs old50-69 yrs old Irrespective of addition of TamIrrespective of addition of Tam Node Positive/Node NegativeNode Positive/Node Negative ER –ve or ER ? Greatest advantageER –ve or ER ? Greatest advantage Offering CT to ER+ pts considerOffering CT to ER+ pts consider

– Pt/tumor characteristicsPt/tumor characteristics– Co morbid conditionsCo morbid conditions


Which Chemotherapy?Which Chemotherapy?


Standard regimens consist ofStandard regimens consist of– CMF/Anthracycline based CTCMF/Anthracycline based CT

Anthracyclin vs CMF Anthracyclin vs CMF – 4% absolute reduction as compared to CMF for 4% absolute reduction as compared to CMF for

death and recurrencedeath and recurrence In node negative setting (1.7%) ? Less In node negative setting (1.7%) ? Less

benefitbenefit Both regimens have toxicityBoth regimens have toxicity

Piccart M et al: ASCO Education Book 2002; 144


Anthracycline basedAnthracycline based– Premenopausal womenPremenopausal women

Node positiveNode positive Node negative high riskNode negative high risk

CMFCMF– In patientsIn patients

With high risk of cardio toxicityWith high risk of cardio toxicity Low risk diseaseLow risk disease

Piccart M et al: ASCO Education Book 2002; 144

Which Chemotherapy?Which Chemotherapy?Taxanes vs no TaxanesTaxanes vs no Taxanes CALGB Trial 9344CALGB Trial 9344

– DFS increased in Node+ve pts ACx4+Tx4DFS increased in Node+ve pts ACx4+Tx4– Reanalysis- Benefit only in ER-ve ptsReanalysis- Benefit only in ER-ve pts

NSABP B-28NSABP B-28– ACx4+Tx4 no benefitACx4+Tx4 no benefit

Br C Int Res Gp 001 (33 months FU)Br C Int Res Gp 001 (33 months FU)– FAC vs TACFAC vs TAC– TAC improved DFS and OS TAC improved DFS and OS – Advantage in 1-3 node +ve ptsAdvantage in 1-3 node +ve pts

No established role yet as adjuvantNo established role yet as adjuvantPiccart M et al: ASCO Education Book 2002; 144

Chemotherapy- Optimum Dose?Chemotherapy- Optimum Dose?

CMFCMF 2 trials I/V CMF 3 vs 62 trials I/V CMF 3 vs 6

– Equivalent Equivalent – Short follow upShort follow up

IBCSG Oral CMF 3 vs 6 cyclesIBCSG Oral CMF 3 vs 6 cycles– CMF x6 betterCMF x6 better

Oral CMF better?Oral CMF better? Reserve I/V cyclo for non toleranceReserve I/V cyclo for non tolerance

Hortobagyi IC st al: J Natl Cancer Inst Monogram 2001; 30:72

Chemotherapy-Optimum Dose/Cycles?Chemotherapy-Optimum Dose/Cycles?

AnthracyclinesAnthracyclines NSABP B-15 & B-23NSABP B-15 & B-23

– 4 cycles AC equivalent to CMF4 cycles AC equivalent to CMF Canadian Trial Canadian Trial

– CEFx6 vs CMFx6CEFx6 vs CMFx6– CEF betterCEF better

Two populations of br ca-peak incid of Two populations of br ca-peak incid of recurrecur– 2 years2 years– 5 years 5 years

6 cycles important in former6 cycles important in former Superiority of Anthracycline regimen in 3 Superiority of Anthracycline regimen in 3

drug combinationsdrug combinations In non high risk patients 4 (F)AC or 6 CMF In non high risk patients 4 (F)AC or 6 CMF

may be enoughmay be enough In high risk patients 6 FAC (FEC)In high risk patients 6 FAC (FEC)

Chemotherapy-Optimum Dose/Cycles?Chemotherapy-Optimum Dose/Cycles?

Chemotherapy When to Start?Chemotherapy When to Start?

IBCSG Trials reviewIBCSG Trials review ER –ve ptsER –ve pts

– Within 21 days of surgery 10 yr DFS 60%Within 21 days of surgery 10 yr DFS 60%– After 21 days 10 yr DFS 34 %After 21 days 10 yr DFS 34 %

ER positive pts no differenceER positive pts no difference Should be instituted within 4-6 (12) wks of Should be instituted within 4-6 (12) wks of

surgerysurgery

Tamoxifen+ ChemotherapyTamoxifen+ Chemotherapy

Postmenopausal womenPostmenopausal women CT+Tam have additive effect?CT+Tam have additive effect? In ER+ pts no definite added benefit In ER+ pts no definite added benefit

confirmedconfirmed– Trials are on stillTrials are on still– In high risk patients CT may be added to In high risk patients CT may be added to

hormonal agenthormonal agent Keep in mind the benefit and toxicityKeep in mind the benefit and toxicity

Tamoxifen+ ChemotherapyTamoxifen+ Chemotherapy

Premenopausal womenPremenopausal women Trials are on to answer this questionTrials are on to answer this question Overview found a highly significant surv Overview found a highly significant surv

benefitbenefit Side effects are lowSide effects are low May be given pending the results of the May be given pending the results of the

trialstrials In node –ve low risk Tam or noneIn node –ve low risk Tam or none

Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit?

Oxford Review 2000 OA added to CTOxford Review 2000 OA added to CT Non significant increase in death Non significant increase in death Non significant decrease in recurrence rateNon significant decrease in recurrence rate Three Randomized trialsThree Randomized trials

– Intergroup 0100 CAFx6 vs CAF+Z (+/- Tam to Intergroup 0100 CAFx6 vs CAF+Z (+/- Tam to either)either)

– CAF+Z+T improved survivalCAF+Z+T improved survival– CAF+Z vs CAF no differenceCAF+Z vs CAF no difference

Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit? IBCSG Trial VIIIIBCSG Trial VIII

– Node –ve/any receptorNode –ve/any receptor– CMFx6 vs Gx18 vs CMF+GCMFx6 vs Gx18 vs CMF+G– Equivalence in ER +ve ptsEquivalence in ER +ve pts

ZIPP TrialZIPP Trial– Tam vs No TamTam vs No Tam– Z vs No ZZ vs No Z– CT vs No CTCT vs No CT– Addition of Z betterAddition of Z better– Reanalysis-no improvement in pts who had Reanalysis-no improvement in pts who had

CT+TamCT+Tam

Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit?

In view of the available data this cannot be recommended at this stage

Predictive Markers Do We Have?Predictive Markers Do We Have?

9 large and many small trials9 large and many small trials Suggested a predictive factorSuggested a predictive factor

– Neu/erb2Neu/erb2– Over expression CMF does not workOver expression CMF does not work– Over expression low or mod dose CAF does not Over expression low or mod dose CAF does not

workwork Relation to response to TamRelation to response to Tam

– Conflicting reportsConflicting reports

Pritchard KI: ASCO Education Book 2002; 161

Predictive Markers Do We Have?Predictive Markers Do We Have?


Endocrine non Responsive

Chemotherapy

Endocrine Responsive

Node negative

Minimal /lowrisk

Average/high risk

OA+TamCT+TamTamOA

Tam

Nil

PostmenopTamTam+CT

Premenop

Node positive

CT+TamOA+Tam

PostmenopTamTam+CT

Premenop


Unsolved ProblemsUnsolved Problems Elderly patients HR-veElderly patients HR-ve < 1 cms tumor size< 1 cms tumor size Average/high risk node negative HR+Average/high risk node negative HR+

– OA/CT/TamOA/CT/Tam Post CT OA in premenopausal HR+ Post CT OA in premenopausal HR+

patientspatients

Health & Medicine

Standard care for breast cancer medical therapy