Overview of Neoadjuvant Chemotherapy in Breast Cancer Dr. Vinod Raina MD, FRCP Professor of Medical Oncology All India Institute of Medical Sciences New Delhi These Power Point presentations are free to download only for academic purposes, with due acknowledgements to authors and this website.
Suggest a new term: Primary Systemic Therapy (PST) • Refers to post diagnosis systemic therapy • Takes into account order of administration, intended subsequent treatment and efficacy of systemic intervention • Other terms used are down staging, induction therapy, preoperative systemic therapy, neoadjuvant chemotherapy. Kaufmann JCO 2003 International Expert Panel
Clinical rationale for increasing use of neoadjuvant chemotherapy • Studies in experimental tumour models • Excellent 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 cancer • Breast-conservation possible
PST; For whom it is standard of care? • For patients with inoperable breast cancer • inflammatory breast cancer • involvement of ipsilateral supra or infraclavicular nodes i.e. N3 disease. stages IIIA-B or T3-4 disease ?
Locally advanced breast cancer • In India it forms 30 % of all breast cancers at some centers. Our own data at AIIMS 1998
For 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 AST • For 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.
PST; • 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 resistance • pCR may be used as a surrogate for survival, less cumbersome than overall survival and less time consuming.
p Complete (n=63) 9% 4% p Non-Invasive (n=26) 23% p Invasive (n=160) NSABP B-18Clinical and Pathological Responses Clinical responses 36% cCR (249 patients) cPR (296 patients) 43% cSD + cPD (140 patients) 20% (number of patients=658)
NSABP B18Overall survival and response to chemotherapy 5yr survival • Path CR = 87% • Clin PR = 68% • Clin NR = 64% p<0.0001 Data from: Fisher et al, J Clin Oncol 1988; 16: 2672-2685
NSABP B-18: updated results. • In pre-op arm 36 % patients had a complete clinical response • Axillary node down staging in preop. patients 59% vs. 42 % path negative nodes • Highly significant correlation between tumor response and path nodal status. • 87 % patients with complete clinical response had path neg nodes • More likely to have lumpectomy 68% vs. 59 %, statistically not different • No difference in disease free and overall survival
Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer Author Local Distant Breast And No.of Follow-up Failure Failure Survival Conservation Group Patient Stage (months) Rate Rate Rate (PST vs. AST) Fisher, NASBP 1,523 T1-3, N0-1, M0 96 * * * 67% versus 60% P=0.002 Gianni, ECTO 892 T1-3, N0-1, M0 23 NA NA NA 71% versus 35% P < 0.0001 Van der Hage, 698 T1c-4d, N0-1, M0 56 * * * 37% versus 21% Eortc NA Jakesz, ABCSG 423 T1-3, N0-2, M0 NA ‡ * * *NA Scholl, S6 390 T2-3, N0-2, M0 66 * * * 82% versus 77% *No Statistical difference
B-18 trial: unanswered questions. • Is there a need for further chemotherapy • Those who show a good response may not require further treatment and those who show a poor response may require different drugs.
Whether favorable prognosis warrants exposure to known toxicity of treatment • B 20 showed that adding adjuvant chemotherapy in node negative women improved disease free survival significantly • NSABP 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.
PST; Which regimen and how much • Anthracycline based chemo was standard, but changing fast • A minimum of 3-4 cycles, additional cycles may be considered for responding patients to maximize response and to improve chances of breast conservation • Use 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.
PST: Rate of successful breast –conservation surgery • It correlates with clinical response and size of the primary tumor • Patients 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)
Local recurrence after BCT • 5-6% in those who achieve CR • 9.7% in those who do not achieve CR • Local recurrence did not correlate with the size of the primary tumor before treatment • Poor response to PST is a predictor of poor prognosis and high risk of recurrence • A demonstrable response may have a positive outcome on the psyche
PST; 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 trials • Smith 2002 JCO.
PST: How should the diagnosis be confirmed before PST • Core biopsy most appropriate • Highest diagnostic accuracy by doing three biopsies, 14 gauge needle
PST; 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 importance • Data not clear reg. need for axillary biopsy or sentinel node before chemotherapy.
Can breast conservation be increased by PST ? (RCTs of neoadjuvant vs adjuvant chemotherapy)
How, when and how often should the effect of PST be monitored • Palpation of lump and axillary nodes at the start of each cycle • Mammography and ultrasound are additional tools • MRI and PET of the breast being studied
How should tumor location be documented • Collaboration of surgical, medical oncologist and radiologist • Two major problems can occur: • Either a very quick and complete response so that the primary lesion cant be identified • Or 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 tattoo • Stereo-tactic localization using mammography is another option • Complete pathological CR becoming more common, so it could become a major issue .
PST; Surgical treatment of the tumor • To obtain clear margins of > 1 mm • No compromise should be made on surgical margins to obtain better cosmetic result • No difference in PST and AST in 8 year local recurrence rates • Patients 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 recurrence • There is an increased rate of second surgical procedures.
Role of Postoperative chemotherapy after PST • Till date no data to support or negate the use of chemotherapy after PST • Data may become available from NSABP B 27 or from • European Cooperative trial in Operable Breast Cancer
PST:When and where should postoperative radiotherapy be administered • Same indications as for adjuvant treatment • Decision should be based on pre-PST findings. • No definitive data on the importance of nodal status after PST and need for axillary radiotherapy • Radiotherapy is not a substitute to surgery, loco-regional control is inadequate when patient is treated with RT alone.
PST: Unresolved issues. • New compounds that are directed against specific molecular targets need to be tested in this setting. • Axillary nodal issue still not convincingly resolved But it is here to stay
Rationale for the use of Docetaxel in PST • Activity in anthracycline-resistant MBC • Superior activity observed in patients with poor prognosis disease • Most effective drug in first-line MBC (single, combined) • No cardio toxicity as with paclitaxel • More lab & clinical activity in breast cancer than paclitaxel • Longer half life than paclitaxel
Important questions for Docetaxel • Does the addition of Docetaxel to an anthracycline-containing regimen have beneficial effects? • Clinical and pathological responses • Breast conservation • Survival • Should 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?
Tax301 StudyConducted by the Aberdeen Breast Group First Phase Second phase 4 cycles of Taxotere All Patients No Response Final Assessment / Surgery 4 cycles of CVAP Response 4 cycles of Taxotere Randomise 4 cycles of CVAP Smith et al, JCO 2002
Aberdeen Tax 301Objective clinical response rates1st phase: 4 cycles CVAP ORR - 67% N=162 patients; 4 cycles of CVAP given to all patients
Aberdeen Tax301Objective clinical response rates2nd phase: responding patients * p=0.03
Aberdeen Tax 301Objective clinical response rates2nd phase: non-responding patients ORR - 47% N=55 patients; additional 4 cycles of Taxotere given
100 Taxotere CVAP 80 60 % of patients 40 20 0 Conservation Mastectomy Type of surgery Aberdeen Tax301 Type of surgery undertaken Breast conservation surgery Taxotere 67% CVAP 48% (p<0.01)
Median Follow - up: 60 months 1.0 97% Survival probability 0.9 78% Taxotere 0.8 CVAP Log rank p=0.04 0.7 20 40 60 80 100 Tax 301 Overall Survival Time (months)
NSABP B-27 ( 2411 pts ) Operable Breast Cancer Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Taxotere x 4 Surgery Taxotere x 4 Surgery Bear et al, J Clin Oncol 2003; 21
NSABP B-27 Clinical Response p < 0.001 cCR cPR cNR 100 40% 80 65% % 60 40 45% 26% 20 14% 9% 0 AC N=1502 AC Taxotere N=687
Non-Invasive No Tumour NSABP B-27 Pathological Response (pCR) in Breast 30 p < 0.001 20 18.9% 26.1% 9.8% 10 13.7% 7.2% 3.9% 0 AC N=1567 AC Taxotere N=786 Adapted from Bear et al, J Clin Oncol 2003; 21
NSABP B-27:Proportion of Patients with negative axillary lymph nodes 80 60 % 58.2 40 p < 0.001 50.8 20 0 AC Taxotere N=752 AC N=1534 Bear et al, J Clin Oncol 2003; 21
NSABP B-27: Breast Conservation 80 60 % 63 61 40 p = 0.70 20 0 AC Taxotere N=718 AC (N=1492) Bear et al, J Clin Oncol 2003; 21
GEPARDUO trial Geparduo AT + Tam Surgery (N=913) T 2 cm (stage I,II) Surgery AC-T +TAM Adriamycin Taxotere Adriamycin Cyclophosphamide von Minckwitz et al., J Clin Oncol 1999 von Minckwitz et al., J Clin Oncol 2001 Taxotere
Treatment regimens 4 cycles AC followed by 4 cycles of Taxotere • Doxorubicin 60 mg/m² (day 1 q 22) • Cyclophosphamide 600 mg/m² (day 1 q 22) • Taxotere 100 mg/m² (day 1 q 22) 4 cycles AT • Doxorubicin 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 time Adapted from G.Raab – SABCS ’03, Abs#241, Poster
Clinical responses in the breast 100% 32.5% 80% 57.4% Complete 60% Partial 44.7% Stasis 40% Progress 29.4% 20% 10.1% 21.1% 0% AT AC-T (n=425) (n=421)
GEPAR-DUO Pathologic Complete Remission (pCR) No Tumor In situ residuals only 30% P < 0.001 20% 16.1% 22.4% 10% 7.7% 11.5% 6.3% 3.8% 0 AT (443pts) AC Taxotere (442 pts) Adapted from G.Raab – SABCS ’03, Abs#241, Poster
Effect on tumour in axillary lymph nodes 80% 60% 60.7% 55.4% 40% 20% 0 AT (n=443) AC Taxotere (n=442)
GEPAR-DUO Effect on breast conservation surgery 80% 74.9% 60% 65.5% 40% 20% 0 AT (n=443) AC Taxotere (n=442)