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Overview of Neoadjuvant Chemotherapy in Breast Cancer Dr. Vinod Raina MD, FRCP Professor of Medical Oncology All India Institute of Medical Sciences New.

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Presentation on theme: "Overview of Neoadjuvant Chemotherapy in Breast Cancer Dr. Vinod Raina MD, FRCP Professor of Medical Oncology All India Institute of Medical Sciences New."— Presentation transcript:

1 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.

2 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

3 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

4 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 ?

5 Locally advanced breast cancer In India it forms 30 % of all breast cancers at some centers. Our own data at AIIMS 1998

6 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.

7 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.

8 NSABP B-18 Clinical and Pathological Responses 36% 20% 43% cCR (249 patients) cPR (296 patients) cSD + cPD (140 patients) 4% p Non- Invasive (n=26) 9% p Complete (n=63) 23% p Invasive (n=160) Clinical responses (number of patients=658)

9 NSABP B18 Overall 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

10 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

11 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% EortcNA Jakesz, ABCSG 423 T1-3, N0-2, M0 NA  ‡ * **NA Scholl, S6 390 T2-3, N0-2, M0 66 * * * 82% versus 77% Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer *No Statistical difference

12 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.

13 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.

14 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.

15 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)

16 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

17 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.

18 PST: How should the diagnosis be confirmed before PST Core biopsy most appropriate Highest diagnostic accuracy by doing three biopsies, 14 gauge needle

19 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.

20 Can breast conservation be increased by PST ? (RCTs of neoadjuvant vs adjuvant chemotherapy)

21 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

22 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.

23 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.

24 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

25 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.

26 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

27 Role of Docetaxel in neo-adjuvant therapy for breast cancer

28 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

29 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?

30 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPARDUO

31 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

32 4 cycles of Taxotere 4 cycles of CVAP No Response Response Randomis e All Patients 4 cycles of CVAP First Phase Smith et al, JCO 2002 Tax301 Study Conducted by the Aberdeen Breast Group Second phase 4 cycles of Taxotere Final Assessment / Surgery

33 Aberdeen Tax 301 Objective clinical response rates 1st phase: 4 cycles CVAP ORR - 67% N=162 patients; 4 cycles of CVAP given to all patients

34 Aberdeen Tax301 Objective clinical response rates 2nd phase: responding patients * p=0.03

35 Aberdeen Tax 301 Objective clinical response rates 2nd phase: non-responding patients ORR - 47% N=55 patients; additional 4 cycles of Taxotere given

36 Aberdeen Tax301 Type of surgery Aberdeen Tax301 Type of surgery undertaken Breast conservation surgery Taxotere 67% CVAP 48% ConservationMastectomy 0 20 40 60 80 100 Taxotere CVAP Type of surgery % of patients (p<0.01)

37 Tax 301 Overall Survival Time (months) Median Follow - up: 60 months Survival probability 1.0 0.9 0.8 0.7 20406080100 Log rank p=0.04 Taxotere CVAP 97% 78%

38 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

39 NSABP B-27 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 Surgery Bear et al, J Clin Oncol 2003; 21 ( 2411 pts )

40 40% 45% 100 80 60 40 20 0 % p < 0.001 ACN=1502 AC Taxotere N=687 65% 26% NSABP B-27 Clinical Response cCRcPRcNR 14% 9%

41 NSABP B-27 Pathological Response (pCR) in Breast p < 0.001 AC Taxotere N=786 AC N=1567 3.9% 9.8% 7.2% 18.9% 20 10 0 30 No Tumour Non-Invasive 26.1% 13.7% Adapted from Bear et al, J Clin Oncol 2003; 21

42 NSABP B-27: Proportion of Patients with negative axillary lymph nodes 58.2 p < 0.001 ACN=1534 AC Taxotere N=752 80 60 40 20 0 % 50.8 Bear et al, J Clin Oncol 2003; 21

43 : Breast Conservation NSABP B-27: Breast Conservation p = 0.70 61 63 80 60 40 20 0 % AC(N=1492) AC Taxotere N=718 Bear et al, J Clin Oncol 2003; 21

44 Neoadjuvant Taxotere The Aberdeen Trial NSABP B27 GEPAR-DUO

45 GEPARDUO trial von Minckwitz et al., J Clin Oncol 1999 von Minckwitz et al., J Clin Oncol 2001 Surgery Geparduo T  2 cm (stage I,II) (N=913) (N=913) AT + Tam AC-T +TAM AdriamycinTaxotere AdriamycinCyclophosphamide Taxotere

46 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

47 0% 20% 40% 60% 80% 100% ATAC-T Complete Partial Stasis Progress (n=421) (n=425) 57.4% 32.5% 29.4% 44.7% 10.1% 21.1% Clinical responses in the breast

48 GEPAR-DUO Pathologic Complete Remission (pCR) P < 0.001 No Tumor In situ residuals only AC  Taxotere (442 pts) AT (443 pts) 3.8% 7.7% 6.3% 16.1% 11.5% 22.4% 20% 10% 0 30% Adapted from G.Raab – SABCS ’03, Abs#241, Poster

49 Effect on tumour in axillary lymph nodes 60.7% 55.4% 60% 40% 20% 0 AT (n=443) 80% AC  Taxotere (n=442)

50 80% 74.9% 65.5% 60% 40% 20% 0 AT (n=443) AC  Taxotere (n=442) GEPAR-DUO Effect on breast conservation surgery

51 AC->Taxotere :  Increased Complete Clinical response  Increased pCR rates  Increased number of patients with no axillary node involvement  Increased breast conservation GEPAR-DUO : Conclusions

52 Author Clinical Pathologic Breast And No.of Complete Response* Conservation Group Patient Stage Regimen Response(%) (%) Rate NSABP 2,411T1-3, N0-1, M0AC x 4 40 9.8 61 AC x 4, Doc x 4 65 18.7 63 Von Minckwitz913T2-3, N0-2, M0AT x 4 q2w 32.5 7.7 65 GABGAC x 4, Doc x 4 57.4 16.1 75 Untch, AGO 475†T2-4d, N0-2, M0ET x 4 NA 10 55 Epi x 3, Tax x 3 q2w 18 66 Von minckwitz248T2-3, N0-2AT x 4 q2w 5.7 10.3 69 GABG AT x 4 q2w + Tam 12.5 9.1 69 Penault-Llorca 200‡NAAC NA 6 45 FranceAT 15 56 Buzdar 174T1-3, N0-1, M0FAC x 4 24 18 35 HoustonTax x 4 27 6 46 Smith 104T2-4, N0-2, M0CVAP x 8 33 15.4§ 48 CVAP x 4, Tax x 4 56 30.8§ 67 Overview of Rand. Trial comparing different Primary Systemic Therapy Regimens in Breast Cancer *No invasive or in situ tumor cells in the removed breast

53 Summary neoadjuvant Taxotere Taxotere offers meaningful benefits to patients:  Highly effective in reducing tumour size  Increases clinical responses  Increases complete pathological response  Increases Nodal clearance  Increases breast conservation  Improved survival in Aberdeen trial  Potential for non-anthracycline combinations

54 Primary Systemic Chemotherapy It is here to stay Effective, improved results in combination Increased rates of breast conservation Better cosmesis Surrogate marker of improved survival Rescue measures can be taken early rather than late

55 PST; Drawbacks Pathological staging not available Improved survival not proven Whether post operative chemotherapy is beneficial not known Can create problems in Radiotherapy Newer options: AI, Trastuzumab

56 Thanks

57 Adjuvant vs neoadjuvant chemotherapy in breast cancer: randomised studies same84 vs 82T0 - T4309Makris, 1998 86 vs 78*59 vs 55IIa - IIIa414Scholl, 1994 86 vs 7881 vs 72*IIb,IIIa271 Semiglazov, 1994 54 vs 55sameT2,T369 Mauriac, 1999 73 vs 72NRI,II204 Ragaz, 1999 OS (%) DFS( %) StageNo. pts Study Fisher, 1998 1523T1 - T3 67 vs 6780 vs 80 (Data from: Wolf and Davidson, J Clin Oncol 2000; *p<0.05)

58 PST: Endocrine therapy remains attractive When it is desirable to avoid chemotherapy As a second choice for selected patients, elderly women with impaired organ function or low PS, or high surgical risk A positive ER, PgR is a requisite. AI more active and better tolerated, thus preferred in postmenopausal patients. No data in premenopausal patients.

59 Locally advanced breast cancer  Increased public awareness, national breast screening  10-20% of patients - LABC (T3, T4 or N2) Haagensen & Stout, 1943  48% local recurrence  3% 5 year survival If radical mastectomy performed }

60 Alternative treatment strategies for LABC  Radiotherapy  Chemotherapy  Chemoradiotherapy  Clinical responses of 60-70% with various chemotherapies

61 Pathological complete response (pCR) in neoadjuvant Taxotere studies 13% (B18) * * * ** *pCR incorporates lymph nodes single agent concurrentsequential

62 Pathological Response and Survival (Miller and Payne grading system) 5 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0 20 40 60 80 100 120 months survival p=0.003* 4 3 2 1 Ogston et al, 2003

63 Aberdeen Tax301 Pathological responses Hutcheon et al, SABCS 2003 *p=0.06 5 19% pNR pCR 31%*15%15% 17%17%15%15%4 23%27%27%3 17%19%19%2 2%2% 1 Taxotere n = 52 CVAP n = 52 Miller & Payne Grade of Pathological Response

64 NSABP B18: Updated results  Still no difference in overall survival  Pathological complete response - 85% year survival at 9 years 67% vs 75%56% vs 60%50 and over 71% vs 65%55% vs 46%49 and under OS Neoadj vs adj DFI Neoadj vs adj Age Wolmark et al, 2001

65 NSABP B-27 trial All patients receive initial AC chemo Group I; No further treatment Group II: 4 cycles of Docetaxel after surgery Group III: 4 cycles of Docetaxel before surgery

66 NSABP-B27 Clinical complete response rates 36-40% vs 65 % Path CR 9 % and 18 %

67 PST:Is there a role for endocrine treatment alone Conventionally response rates with endocrine therapy are far inferior In 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.

68 Aberdeen Tax301 2nd phase: non-responding patients 5 15 pNR pCR 1 64 133 112 1 Taxotere n = 46 Miller & Payne Grade of Pathological Response 20 (44%) patients had a grade 3,4 or 5 response

69 Taxotere and paclitaxel Similar mechanisms of action, but some differences Taxotere has:  Greater affinity for tubulin  Longer half-life  Longer intracellular retention  Lower cardio toxicity with doxorubicin

70 PST: scientific basis Pulmonary metastases in animals underwent growth spurt on removal of primary tumor, this can be overcome by prior chemotherapy Growth fractions in cell populations suggest micro metastases might respond differently to preoperative chemotherapy Goldie–Coldman hypothesis suggests that resistance to chemotherapy was a function of time, hence early treatment might be better.

71 TAX 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 CVAP  pCR of 31% (ITT analysis)  increased 5 year DFS and Survival  Achieve a higher rate of Breast conservation

72 Patients unresponsive to primary CVAP chemotherapy receiving further sequential Taxotere achieve : –47% Clinical ORR –1 Complete pathological response TAX 301 Study Conclusions

73 NSABP B-27 : Conclusions  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% ) The addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of:

74 PST; Early rand. trial Scholl et al from Institut Curie 414 premenopausal women, T2,T3,N0-N1 4 cycles CAF followed by RT (surgery only for those who did not have CR) VS Surgery followed by 4 cycles of same chemo FU 54 months OS better in primary chemo arm, no difference in disease free survival or local recurrence

75 Bordeaux trial 272 women with lesions more than 3 cms rand between mastectomy and chemo if nodes positive VS initial chemotherapy followed by RT/ surgery 34 months FU patients with initial chemo better overall survival, however more isolated recurrence occurred in these patients.

76 79% (B18) 29% of tumours < 2cm in the B18 study single agent concurrentsequential Clinical response rates in neoadjuvant Taxotere studies

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