Presentation on theme: "Overview of Neoadjuvant Chemotherapy in Breast Cancer"— Presentation transcript:
1Overview of Neoadjuvant Chemotherapy in Breast Cancer Dr. Vinod Raina MD, FRCPProfessor of Medical OncologyAll India Institute of Medical SciencesNew DelhiThese Power Point presentations are free to download only for academic purposes, with due acknowledgements to authors and this website.
2Suggest a new term: Primary Systemic Therapy (PST) Refers to post diagnosis systemic therapyTakes into account order of administration, intended subsequent treatment and efficacy of systemic interventionOther terms used are down staging, induction therapy, preoperative systemic therapy, neoadjuvant chemotherapy.Kaufmann JCO International Expert Panel
3Clinical rationale for increasing use of neoadjuvant chemotherapy Studies in experimental tumour modelsExcellent clinical response rates in locally advanced breast cancer (T3,T4 or TxN2)Pathological CRs of up to 15%Adjuvant chemotherapy has survival benefit in node positive and negative breast cancerBreast-conservation possible
4PST; For whom it is standard of care? For patients with inoperable breast cancerinflammatory breast cancerinvolvement of ipsilateral supra or infraclavicular nodes i.e. N3 disease.stages IIIA-B or T3-4 disease ?
5Locally advanced breast cancer In India it forms 30 % of all breast cancers at some centers.Our own data at AIIMS 1998
6For whom can PST be recommended as an alternative to AST ? Most large randomized trials of PST versus AST indicate that these therapies offer equivalent disease free and overall survival benefits.For operable breast cancer, PST can be considered as an alternative to ASTFor patients who are deemed appropriate candidates for mastectomy but who desire less extensive surgery (breast conservation surgery). Success rate 5-36 %.Also in patients who can technically have a lumpectomy first but whose physical appearance will be less damaged if PST is given first.
7PST;May also be advisable in patients who have medical contraindications to surgery or if they simply wish to delay surgery i.e. pregnant patient diagnosed in second and third trimester.PST offers an optimal test situation for evaluation of new compounds and detection of new biologic or molecular discriminants of either response or resistancepCR may be used as a surrogate for survival, lesscumbersome than overall survival and less time consuming.
8NSABP B-18 Clinical and Pathological Responses Clinical responses9%p Complete(n=63)36%cCR(249 patients)4%p Non-Invasive(n=26)23%p Invasive(n=160)cPR(296 patients)43%cSD + cPD(140 patients)20%(number of patients=658)
9NSABP B18 Overall survival and response to chemotherapy 5yr survivalPath CR = 87%Clin PR = 68%Clin NR = 64%p<0.0001Data from: Fisher et al, J Clin Oncol 1988; 16:
10NSABP B-18: updated results. In pre-op arm 36 % patients had a complete clinical responseAxillary node down staging in preop. patients 59% vs. 42 %path negative nodesHighly significant correlation between tumor responseand path nodal status.87 % patients with complete clinical response hadpath neg nodesMore likely to have lumpectomy 68% vs. 59 %,statistically not differentNo difference in disease free and overall survival
11Author Local Distant Breast And No.of Follow-up Failure Failure Survival ConservationGroup Patient Stage (months) Rate Rate Rate (PST vs. AST)Fisher, NASBP , T1-3, N0-1, M * * * % versus 60% P=0.002Gianni, ECTO T1-3, N0-1, M NA NA NA % versus 35% P <Van der Hage, T1c-4d, N0-1, M * * * % versus 21% Eortc NAJakesz, ABCSG T1-3, N0-2, M NA ‡ * * *NAScholl, S T2-3, N0-2, M * * * % versus 77%Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer*No Statistical difference
12B-18 trial: unanswered questions. Is there a need for further chemotherapyThose who show a good response may notrequire further treatment and those who showa poor response may require different drugs.
13Whether favorable prognosis warrants exposure to known toxicity of treatment B 20 showed that adding adjuvant chemotherapy in node negative women improved disease free survival significantlyNSABP B20 trial removes possible concerns about preoperative chemotherapy in patients with favorable tumor size, receptor status and histology.General consensus: that there is no group that is not benefited by chemotherapy: very small palpable tumors, node positive and negative, ER positive and negative, all benefit.
14PST; Which regimen and how much Anthracycline based chemo was standard, but changing fastA minimum of 3-4 cycles, additional cycles may be considered for responding patients to maximize response and to improve chances of breast conservationUse of Taxanes and sequential therapies can increase rate of pCR / successful breast conservation surgery / node negative patients by 50%.Trastuzumab and other targeted therapies are under investigation.
15PST: Rate of successful breast –conservation surgery It correlates with clinical response and size of the primary tumorPatients with a complete clinical response may have a successful breast conservation rate of 90 %.In the largest trial so far no statistically significant difference was found in local recurrence free survival between patients treated with PST (4 cycles of AC) and those treated with AST (4 cycles of AC)
16Local recurrence after BCT 5-6% in those who achieve CR9.7% in those who do not achieve CRLocal recurrence did not correlate with the sizeof the primary tumor before treatmentPoor response to PST is a predictor of poor prognosis and high risk of recurrenceA demonstrable response may have a positive outcome on the psyche
17PST; poor response Immediate surgical intervention is indicated? Alternative chemotherapy i.e. non cross resistant agents like Taxanes an obvious choice, about 50 % patients can respond but require close monitoring.Trastuzumab and other new targeted therapies are still under investigation and should not be used outside clinical trialsSmith 2002 JCO.
18PST: How should the diagnosis be confirmed before PST Core biopsy most appropriateHighest diagnostic accuracy by doingthree biopsies, 14 gauge needle
19PST; Should markers be assessed before PST Typing of tumor and assessment of surgical grade impossible because of changes due to chemo, hence preferably to be done on core tissue .Similarly ER/ PR and Her 2 or Ki67 to be done on core tissue before PST.Pathological nodal status is not available reg. prognosis and radiotherapy (a major drawback)However pathological nodal status after PST of relevant prognostic importanceData not clear reg. need for axillary biopsy or sentinel node before chemotherapy.
20Can breast conservation be increased by PST ? (RCTs of neoadjuvant vs adjuvant chemotherapy)
21How, when and how often should the effect of PST be monitored Palpation of lump and axillary nodes at the start of each cycleMammography and ultrasound are additional toolsMRI and PET of the breast being studied
22How should tumor location be documented Collaboration of surgical, medical oncologist and radiologistTwo major problems can occur:Either a very quick and complete response so that the primary lesion cant be identifiedOr no response, in that case surgeon may have to intervene.Precise documentation of the tumor on sketch, inserting clips or coils in the center of the lesion or placing a tattooStereo-tactic localization using mammography is another optionComplete pathological CR becoming more common, so it could become a major issue .
23PST; Surgical treatment of the tumor To obtain clear margins of > 1 mmNo compromise should be made on surgical margins to obtain better cosmetic resultNo difference in PST and AST in 8 year local recurrence ratesPatients less than 40 years and those with larger tumors, high rates of tumor proliferation or close or involved margins are at higher risk of local recurrenceThere is an increased rate of second surgical procedures.
24Role of Postoperative chemotherapy after PST Till date no data to support or negate the use of chemotherapy after PSTData may become available from NSABP B 27 or fromEuropean Cooperative trial in Operable Breast Cancer
25PST:When and where should postoperative radiotherapy be administered Same indications as for adjuvant treatmentDecision should be based on pre-PST findings.No definitive data on the importance of nodal status after PST and need for axillary radiotherapyRadiotherapy is not a substitute to surgery, loco-regional control is inadequate when patient is treated with RT alone.
26PST: Unresolved issues. New compounds that are directed against specific molecular targets need to be tested in this setting.Axillary nodal issue still not convincingly resolvedBut it is here to stay
27Role of Docetaxel in neo-adjuvant therapy for breast cancer
28Rationale for the use of Docetaxel in PST Activity in anthracycline-resistant MBCSuperior activity observed in patients with poor prognosis diseaseMost effective drug in first-line MBC (single, combined)No cardio toxicity as with paclitaxelMore lab & clinical activity in breast cancer than paclitaxelLonger half life than paclitaxel
29Important questions for Docetaxel Does the addition of Docetaxel to an anthracycline- containing regimen have beneficial effects?Clinical and pathological responsesBreast conservationSurvivalShould Docetaxel be given concurrently with or following an anthracycline-containing regimen and what is the best schedule?What about role of trastuzumab in HER2 over- expressing tumors?
30Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPARDUO
31Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO
32Tax301 Study Conducted by the Aberdeen Breast Group First PhaseSecond phase4 cycles of TaxotereAll PatientsNo Response4 cycles of CVAPFinal Assessment / SurgeryResponse4 cycles of TaxotereRandomise4 cycles of CVAPSmith et al, JCO 2002
33Aberdeen Tax 301 Objective clinical response rates 1st phase: 4 cycles CVAP ORR - 67%N=162 patients; 4 cycles of CVAP given to all patients
38Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO
39Operable Breast Cancer NSABP B-27( 2411 pts )Operable Breast CancerRandomizationAC x 4Tam X 5 YrsAC x 4Tam X 5 YrsAC x 4Tam X 5 YrsSurgeryTaxotere x 4SurgerySurgeryTaxotere x 4Bear et al, J Clin Oncol 2003; 21
41Pathological Response (pCR) in Breast NSABP B-27Pathological Response (pCR) in BreastNo TumourNon-Invasive30p < 0.0012018.9%26.1%109.8%13.7%7.2%3.9%ACN=1567AC TaxotereN=786Adapted from Bear et al, J Clin Oncol 2003; 21
42NSABP B-27: Proportion of Patients with negative axillary lymph nodes 8060%58.24050.8p < 0.00120ACN=1534AC TaxotereN=752Bear et al, J Clin Oncol 2003; 21
43NSABP B-27: Breast Conservation 8060%636140p = 0.7020AC(N=1492)AC TaxotereN=718Bear et al, J Clin Oncol 2003; 21
44Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO
45Geparduo GEPARDUO trial AT + Tam AC-T +TAM T 2 cm (stage I,II) Surgery(N=913)T 2 cm(stage I,II)SurgeryAC-T +TAMAdriamycinTaxotereAdriamycinCyclophosphamidevon Minckwitz et al., J Clin Oncol 1999von Minckwitz et al., J Clin Oncol 2001Taxotere
46Adapted from G.Raab – SABCS ’03, Abs#241, Poster Treatment regimens4 cycles AC followed by 4 cycles of TaxotereDoxorubicin mg/m² (day 1 q 22)Cyclophosphamide 600 mg/m² (day 1 q 22)Taxotere mg/m² (day 1 q 22)4 cycles ATDoxorubicin 50 mg/m² (day 1 q 15)Taxotere 75 mg/m² (day 1 q 15)G-CSF (days 5-10)Tamoxifen 20mg /day at same timeAdapted from G.Raab – SABCS ’03, Abs#241, Poster
47Clinical responses in the breast 100%32.5%80%57.4%Complete60%Partial44.7%Stasis40%Progress29.4%20%21.1%10.1%0%ATAC-T(n=421)(n=425)
49Effect on tumour in axillary lymph nodes 80%60%60.7%55.4%40%20%AT(n=443)AC Taxotere(n=442)
50Effect on breast conservation surgery GEPAR-DUOEffect on breast conservation surgery80%74.9%60%65.5%40%20%AT(n=443)AC Taxotere(n=442)
51GEPAR-DUO : Conclusions AC->Taxotere :Increased Complete Clinical responseIncreased pCR ratesIncreased number of patients with no axillary node involvementIncreased breast conservation
52Author Clinical Pathologic Breast And No.of Complete Response* ConservationGroup Patient Stage Regimen Response(%) (%) RateNSABP 2,411 T1-3, N0-1, M0 AC xAC x 4, Doc xVon Minckwitz 913 T2-3, N0-2, M0 AT x 4 q2wGABG AC x 4, Doc xUntch, AGO † T2-4d, N0-2, M0 ET x NAEpi x 3, Tax x 3 q2wVon minckwitz 248 T2-3, N0-2 AT x 4 q2wGABG AT x 4 q2w + TamPenault-Llorca ‡ NA AC NAFrance ATBuzdar T1-3, N0-1, M0 FAC xHouston Tax xSmith T2-4, N0-2, M0 CVAP x §CVAP x 4, Tax x §Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast Cancer*No invasive or in situ tumor cells in the removed breast
53Summary neoadjuvant Taxotere Taxotere offers meaningful benefits to patients:Highly effective in reducing tumour sizeIncreases clinical responsesIncreases complete pathological responseIncreases Nodal clearanceIncreases breast conservationImproved survival in Aberdeen trialPotential for non-anthracycline combinations
54Primary Systemic Chemotherapy It is here to stayEffective, improved results in combinationIncreased rates of breast conservationBetter cosmesisSurrogate marker of improved survivalRescue measures can be taken early rather than late
55PST; Drawbacks Pathological staging not available Improved survival not provenWhether post operative chemotherapy is beneficial not knownCan create problems in RadiotherapyNewer options: AI, Trastuzumab
57Adjuvant vs neoadjuvant chemotherapy in breast cancer: randomised studies StudyNo. ptsStageDFS(%)OS (%)Ragaz, 1999204I,IINR73 vs 72Mauriac, 199969T2,T3same54 vs 55Semiglazov,1994271IIb,IIIa81 vs 72*86 vs 78Scholl, 1994414IIa - IIIa59 vs 5586 vs 78*cCR=clinical complete remission in %, pCR=pathological complete remission in %,BST=breast conserving treatmentS=surgery,FECi=5-FU, epirubicin, cisplatinVbEM=vinorelbine,epirubicin,methotrexateFMxC=5-FU, mitoxantrone, cyclophosphamideTAVbCF*=doxorubicin, vinorelbine, cyclosphamide, 5-FU w/wout colony stimulating factorCMF=cyclophosphamide, theotrexate, 5-FUFAC=5-FU, doxorubicin, cyclophosphamideFEC=5-FU, epirubicin, cyclophsphamideA=doxorubicinMakris, 1998309T0 - T484 vs 82sameFisher, 19981523T1 - T367 vs 6780 vs 80(Data from: Wolf and Davidson, J Clin Oncol 2000; *p<0.05)
58PST: Endocrine therapy remains attractive When it is desirable to avoid chemotherapyAs a second choice for selected patients, elderly women with impaired organ function or low PS, or high surgical riskA positive ER, PgR is a requisite.AI more active and better tolerated, thus preferred in postmenopausal patients.No data in premenopausal patients.
59Locally advanced breast cancer Increased public awareness, national breast screening10-20% of patients - LABC (T3, T4 or N2)Haagensen & Stout, 194348% local recurrence3% 5 year survival}If radical mastectomyperformed
60Alternative treatment strategies for LABC RadiotherapyChemotherapyChemoradiotherapyClinical responses of 60-70% with various chemotherapies
62Pathological Response and Survival (Miller and Payne grading system) 51.00.90.80.22.214.171.1243survival2p=0.003*1monthsOgston et al, 2003
63Pathological responses Miller & Payne Grade of Pathological Response Aberdeen Tax301Pathological responsesMiller & Payne Grade of Pathological ResponseCVAPn = 52Taxoteren = 52119%2%pNR219%17%327%23%415%17%pCR515%31%**p=0.06Hutcheon et al, SABCS 2003
64NSABP B18: Updated results Still no difference in overall survivalPathological complete response - 85% year survival at 9 yearsAgeDFINeoadj vs adjOSNeoadj vs adj49 and under55% vs 46%71% vs 65%50 and over56% vs 60%67% vs 75%Wolmark et al, 2001
65NSABP B-27 trial All patients receive initial AC chemo Group I; No further treatmentGroup II: 4 cycles of Docetaxel after surgeryGroup III: 4 cycles of Docetaxel before surgery
66NSABP-B27 Clinical complete response rates 36-40% vs 65 % Path CR 9 % and 18 %
67PST:Is there a role for endocrine treatment alone Conventionally response rates with endocrine therapy are far inferiorIn a largest trial so far of 337 patients, a pCR was observed in only 1.5 % patients. Eiermann et al. Ann Oncol 2001.But things may be changing soon, Aromatase inhibitors have shown better responses in small studies.
682nd phase: non-responding patients Aberdeen Tax3012nd phase: non-responding patientsMiller & Payne Gradeof PathologicalResponseTaxoteren = 46115pNR21131346pCR5120 (44%) patients had a grade 3,4 or 5 response
69Taxotere and paclitaxel Similar mechanisms of action, but some differencesTaxotere has:Greater affinity for tubulinLonger half-lifeLonger intracellular retentionLower cardio toxicity with doxorubicin
70PST: scientific basisPulmonary metastases in animals underwent growth spurt on removal of primary tumor, this can be overcome by prior chemotherapyGrowth fractions in cell populations suggest micro metastases might respond differently to preoperative chemotherapyGoldie–Coldman hypothesis suggests that resistance to chemotherapy was a function of time, hence early treatment might be better.
71TAX 301 Study Conclusions After 4 cycles of CVAP and Taxotere: Increased the complete response rate to 62% in initially responsive patients vs. 34% for continued CVAPpCR of 31% (ITT analysis)increased 5 year DFS and SurvivalAchieve a higher rate of Breast conservation
72TAX 301 StudyConclusionsPatients unresponsive to primary CVAP chemotherapy receiving further sequential Taxotere achieve :47% Clinical ORR1 Complete pathological response
73NSABP B-27 : ConclusionsThe addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of:Clinical Complete Response: 40% vs 65% (63% )Pathologic Complete Response: 13.7% vs 26.1% (91% )Negative Axillary Nodes: 50.8% vs 58.2% (16% )
74PST; Early rand. trial Scholl et al from Institut Curie 414 premenopausal women, T2,T3,N0-N14 cycles CAF followed by RT (surgery only for those who did not have CR) VS Surgery followed by 4 cycles of same chemoFU 54 months OS better in primary chemo arm, no difference in disease free survival or local recurrence
75Bordeaux trial272 women with lesions more than 3 cms rand between mastectomy and chemo if nodes positive VS initial chemotherapy followed by RT/ surgery34 months FU patients with initial chemo better overall survival, however more isolated recurrence occurred in these patients.
76Clinical response rates in neoadjuvant Taxotere studies concurrentsequentialsingle agent79% (B18)29% of tumours < 2cm in the B18 study