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EVOLUTION OF CHEMOTHERAPY IN BREAST CANCER

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Adjuvant Chemotherapy
Neo-adjuvant Chemotherapy
Concurrent Chemotherapy
Chemotherapy In Metastatic Breast Cancer
EBCTCG Overview

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EVOLUTION OF CHEMOTHERAPY IN BREAST CANCER

  1. 1. Chemotherapy in Breast Cancer Presented By: Dr. Isha Jaiswal Moderator: Dr. Neeraj Rastogi Date: 20th February 2017
  2. 2. • Chemotherapy in primary breast cancer • Adjuvant chemotherapy • Neo-adjuvant chemotherapy
  3. 3. Introduction • Breast cancer is a systemic disease • Chemotherapy is an integral part of breast cancer treatment
  4. 4. Adjuvant chemotherapy
  5. 5. RATIONALE FOR ADJUVANT CHEMOTHERAPY • Fisher hypothesis • Gompertzian model
  6. 6. OLD CONCEPT!!! • William S. Halsted • Halsted radical mastectomy • Breast cancer arose in one location and spread to nearby lymph nodes and then throughout the body • So, removal of breast, chest wall muscle, and lymph nodes was the logical treatment.
  7. 7. Bernard Fisher - alternative hypothesis • “Breast cancer is a systemic disease in that, tumor cells were likely to have been disseminated throughout the body by the time of diagnosis and that more expansive locoregional therapy was unlikely to improve survival” ”
  8. 8. Gompertzian model • Benjamin Gompertz • 18th century mathematician “Law of mortality” • Growth rate of populations are exponential at early stages of development and slower at later stages
  9. 9. Norton and Simon hypothesis • Tumors follow Gompertzian growth functions • Smaller tumors grow faster than larger ones • Rate of cell-killing by many drugs is proportional to tumor growth rates • Tumors given less time to regrow between treatments are more likely to be destroyed • Shorten the interval between chemotherapy from 3 weeks to 2 • High-density dosing – Improved survival Dose dense chemotherapy
  10. 10. Trial Year Control arm Treatment arm FU (yr) DFS/RFS OS Bonadonna et al (N-/+) 1976 2005 Surgery alone CMF X 12 20 26% vs 37% (p=S) 24% vs 47% ( p=S) NSABP B-13 (N-) 1996 Surgery alone M F 16 63% vs 77%(p=S) 65% vs 74%(p=S) NSABP B-19 (N-) 1996 M -> F CMF 13 73% vs 83%(p=S) 74% vs 82%(p=NS) NSABP B-23 (N-) 2001 CMF X 6 ± tam AC X 4 ± tam 8 85% vs 85%(p=NS) 85% vs 86%(p=NS) NCIC MA5 (N+) 2005 CMF CEF 10 45% vs 52%(p=S) 58% vs 62(p=NS%) FASG 05(N+) 2001 FEC-50 FEC-100 9.2 45% VS 51%(p=S) 50% VS 55%(p=S) CALGB 9344(N+) 2003 AC dose escalated AC Taxol 5 65% vs 70%(p=S) 77% vs 80%(p=S) NSABP B-28(N+) 2005 AC AC Taxol 5.4 76% vs 72%%(p=S) 85% vs 85%%(p=NS) CALGB 9741(N+) 2003 AC T or A T C q 3 wk AC T or A T C q 2wk 4 75% vs 82% (p=S) 90% vs 92%(p=S) BCIRG 001(N+) 2005 FAC X 6 TAC X 6 4.5 68% vs 75%(p=S) 81% vs 87%(p=S) PACS 01(N+) 2006 FEC X 6 FEC X 3 D X 3 5 73% vs 78%(p=S) 87% vs 91%(p=S) US Oncology 9735(N-/+) 2006 2009 AC X 4 TC X 4 6 79% vs 85% (p=S) 88% vs 84%(p=S) Established the role of polychemotherapy in adjuvant setting Better results with anthracycline based chemotherapy Establish superiority of sequential taxol based combination Dose dense chemotherapy as a alternative strategy Evaluate the efficacy of adjuvant Docetaxel
  11. 11. Bonadonna et al 1976, 2005 RATIONALE: To assess the long term effectiveness of adjuvant treatment with CMF operable breast cancer pts.at risk of relapse, on the basis of three successive RCT and one observational study • Bonadonna G, Brusamolino E,, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405–10. • Bonadonna G, Moliterni A,, et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ. 2005;330:217.
  12. 12. C (100 mg/m2 orally D1-14), Mtx (40 mg/m2 i.v D1-8), and 5FU(600 mg/m2 i.v D1-8), repeated every four weeks for either 6-12 cycles. Design :Cohort Study. Inclusion: Pre & Post Menopausal ,Both MRM & BCS , Node Positive& negative Outcome Measures : Relapse Free(RFS) And Overall Survival (OS), Measured By Univariate And Multivariate Analyses
  13. 13. Median Follow Up = 28.5 Years Adjuvant CMF Was Found To Reduce The Relative Risk Of Relapse Significantly ( P = 0.005) And Death ( P = 0.04). CMF12cycles Equivalent To CMF 6 Cycles. OS ( P = 0.04).RFS ( P = 0.005) RESULTS
  14. 14. NSABP B-13 and NSABP B-19 J Clin Oncol 1996;14:1982–92. Rationale: Compare Mtx & 5FU with conventional CMF in node negative ,estrogen receptor negative breast cancer
  15. 15. NSABP-13 NSABP-19 in patients with estrogen receptor (ER)-negative and negative axillary nodes •760 patients were randomized to B-13 • 1,095 patients with the same eligibility requirements were randomized to B-19. •Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life- table estimates.
  16. 16. RESULTS NSABP B-13 Sx alone Sx + M-->F P value DFS 59% 74% <0.001 ≤49yrs 56% 69% .006 ≥50yrs 63% 81% .002 •NSABP B-13 at 8 years follow up NSABP B-19 M-->F CMF P value DFS 72% 84% <0.001 OS 84% 89% 0.06 The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in ≤49 years. •NSABP B-19 at 5 years follow up
  17. 17. CMF ESTABLISHED AS GOLD STANDARD FOR ADJUVANT CHEMOTHERAPY IN EARLY STAGE BREAST CANCER TILL 1970s
  18. 18. EBCTCG Overview 1988 • Systematic review of adjuvant chemotherapy trials • 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, • Benefit of polychemotherapy (CMF) seen in reducing recurrence & improving survival in women in all ages., unaffected by menopausal status, nodal status or tamoxifen use • recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988;319:1681–92.
  19. 19. EBCTCG Overview 1988 Impact of Age , Nodal & Receptor Status 10 year survival improved by about 10% in the <50 age and about 2-3% in 50-69 age group Impact of chemotherapy more in ER-& node + patients Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988;319:1681–92. • in women under age 50 yrs 10-year survival improved from 71% for node-negative to 78% (an absolute benefit of 7%), and of 42% for node- positive disease to 53% (an absolute benefit of 11%). • in women aged 50–69 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for node-positive disease to 49% (an absolute gain of 3%) • For women age under age 50 yrs reduction in recurrence 40% for ER poor and 33% for ER + • For women age 50-69 yrs reduction in recurrence was 30% for ER poor disease compared with 18% for ER + disease.
  20. 20. Trial Year Control arm Treatment arm FU (yr) DFS/RFS OS NSABP B-23 2001 CMF X 6 ± tam AC X 4 ± tam 8 85% vs 85%(p=NS) 85% vs 86%(p=NS) NCIC MA5 2005 CMF CEF 10 45% vs 52%(p=S) 58% vs 62(p=NS%) FASG 05 2001 FEC-50 FEC-100 9.2 45% VS 51%(p=S) 50% VS 55%(p=S) Introduction of doxorubicin to the polychemotherapy regimen of breast cancer
  21. 21. NSABP B-23 Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23 Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor- negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001;19:931–42. Rationale: Uncertainty about the relative worth of AC and CMF, as well as doubt about the propriety of giving tamoxifen with chemotherapy to patients with estrogen receptor–negative tumors and negative axillary nodes,  Patients (n = 2,008) were randomly assigned to  CMF plus placebo  CMF plus TAM  AC plus placebo  AC plus TAM.  Six cycles of CMF were given for 6 months  four cycles of AC were administered for 63 days.  TAM was given daily for 5 years.  Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates
  22. 22. • No significant difference in RFS, EFS, or OS was observed among the four groups through 5 years • four cycles of AC equivalent to six cycles of CMF regardless of nodal status, age, or estrogen-receptor(ER) status, • AC offered following advantages over CMF shorter treatment course  fewer side effects less hospital visits (4 vs 12) CMF AC P value RFS 87% 87% 0.9 EFS 83% 82% 0.6 OS 89% 90% 0.4 Conclusion:4×AC=6×CMF
  23. 23. NCIC MA5 J Clin Oncol 23:5166-5170, 2005 CEF Cyclophosphamide 75 mg/m2 orally days 1 through 14, Epirubicin 60 mg/m2 intravenously days 1 and 8, Fluorouracil 500 mg/m2 intravenously days 1 and 8 (CEF) or CMF Cyclophosphamide 100 mg/m2 orally days 1 through 14, Methotrexate 40 mg/m2 iv days 1 and 8, Fluorouracil 600 mg/m2 iv days 1 and 8). •Between 1989 and 1993 •710 pre- and peri-menopausal •axillary node–positive
  24. 24. J Clin Oncol 23:5166-5170, 2005 •Primary end point –RFS •Secondary end point –OS & toxicity •trial results updated, at median follow- up 10 years for live patients
  25. 25.  END POINT CMF CEF P value 10-yr RFS 45% 52% 0.007 10-yr OS 58% 62% 0.085 J Clin Oncol 23:5166-5170, 2005 Side effects: rates of acute leukemia similar rates of CHF slightly higher but acceptable (4 pts [1.1%] in CEF v 1pt[0.3%] in CMF Conclusion:CEF significantly improves RFS and trends improved OS in premenopausal node positive patients
  26. 26. Doxorubicin vs Epirubicin • There are no phase III studies comparing epirubicin with doxorubicin as adjuvant therapy at optimal doses of each anthracycline. • However, phase III comparisons of FEC and FAC at the same doses 50 mg/m2 per course in metastatic disease confirm similar efficacy, but consistently demonstrate improved safety for epirubicin* • This low toxicity suggests that higher doses of epirubicin may produce more optimal clinical outcomes. • Escalation of doxorubicin dose does not seem to improve survival** (in CALGB9344 , doses from 60 mg/m2 to 90 mg/m2 administered as adjuvant therapy to women with node-positive primary disease had nearly identical 5-year rates of DFS), • French Adjuvant Study Group 05 (FASG-05) started randomized trial on epirubicin dose escalation *French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6::679,1988-688, ** Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21::976,2003-983
  27. 27. FASG 05:2001,2005 French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2001;19:602–11. Purpose: To determine the influence of the epirubicin dose escalation in operable node- positive breast cancer patients with poor prognosis. April 1990 and July1993, Inclusion:565 operable pts with either • more than three positive nodes •or 1-3 positive nodes with SBR grade > 2 and ER negativity were randomized after surgery to • Arm A:FEC 50 - fluorouracil 500 mg/m2 , epirubicin 50 mg/m2 , cyclophosphamide 500 mg/m2 • Arm B:FEC 100 - fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 cyclophosphamide 500 mg/m2 , End point:DFS & OS Median FU:67 months
  28. 28. Improvement in 5 year DFS & OS was significant especially in patients with more than three positive nodes
  29. 29. Toxicity • FEC 100 was more toxic than FEC 50 • No GCSF support or prophylactic antibiotic • Nine cases of grade 3 infection occurred only with FEC 100 • .Three cases of acute cardiac toxicity were observed (FEC50 = 1, FEC100 = 2) • 10 patients (FEC50 = 6, FEC100 = 4) presented delayed cardiac dysfunctions. • Two cases of secondary leukemia were observed (one with FEC 50 and other with FEC 100 • Conclusion: After 5 years of follow-up, the increased epirubicin dose led to a significant benefit DFS and OS, in patients with poor- prognosis breast cancer
  30. 30. 10 YR RESULTS FEC 50 FEC 100 P value 10 yr DFS 45.3% 50.7% 0.036 10 yr OS 50.0% 54.8% 0.038 P=0.036 P=0.038
  31. 31. Long term toxicity • CARDIAC TOXICITY • Delayed cardiac toxicity (before relapse) occurred in four patients (1.5%) in the FEC 50 arm and three patients (1.1%) in the FEC 100 arm. • Cardiac toxicity after relapse occurred in six (4.3%) and five (4.1%) patients treated with FEC 50 and FEC 100, respectively. • Toxicity consisted of left ventricular dysfunction with or without CHF (n = 8), rhythm disturbances (n = 2), and cardiovascular collapse (n = 1). • additional treatment for metastatic disease might have contributed to the cardiac toxicity • SECOND MALIGNANCIES • total of 27 (10.0%) of 271 patients receiving FEC 50 and 22 (8.3%) of 266 patients receiving FEC 100 experienced second malignancies. • Contralateral breast cancer was reported in 17 women treated with FEC 50 (6.3%) and in nine women treated with FEC 100 (3.4%) • No additional cases of acute myelogenous leukemia were identified between the 5-year and 10-year follow- up
  32. 32. Trial Year Control arm Treatment arm FU (yr) DFS/RFS OS CALGB 9344 2003 AC dose escalated AC Taxol 5 65% vs 70%(p=S) 77% vs 80%(p=S) NSABP B-28 2005 AC AC Taxol 5.4 76% vs 72%%(p=S) 85% vs 85%%(p=NS) ROLE OF TAXANES: PACLITAXEL
  33. 33. • 3,121 women • Node +ve. Stage II-IIIA • 3 X 2 factorial design • Primary end point – DFS • Secondary end point – OS • Median follow up – 69 mnths Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21:976–83. CALGB 9344/Intergroup 0148
  34. 34. No evidence of a doxorubicin dose effect beyond 60 mg/m2/dose
  35. 35. Adding paclitaxel to CA led to hazard reductions of 17% for recurrence (P= 0.0023) ;18% for death (P - 0.0064) Improvement of 5% in disease-free and 3% in overall survival was evident at 5 years. The additional toxicity from adding four cycles of paclitaxel was generally modest Conclusion: addition of four cycles of paclitaxel after standard course of CA improves the disease-free and overall survival of patients with early breast cancer.
  36. 36. • Between August 1995 and May 1998, 3,060 patients resected operable breast cancer and histologically positive nodes were randomly assigned • AC (1,529) • AC followed by PTX (225 mg/m2 ) (1,531). • Post lumpectomy radiotherapy was mandated. • Post mastectomy or regional radiotherapy was prohibited. • Primary end point – DFS • Secondary end point – OS • Median follow-up is 64.6 months. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005;23:3686–96.
  37. 37.  Addition of PTX to AC significant improved DFS but no significant improvement in OS with acceptable toxicity Several explanation hv bn put forth to explain the lack of survival benefit in NSABP trial. pts in this trial were older and had low risk disease compare to CALGB trial. hormone receptor pos pts also receive tamoxifen concurrently which may hv decreased the expected benefit.
  38. 38. ADDITION OF DOCETAXEL
  39. 39. • 18-70 years with node-positive, early breast cancer and a KPS 80% • Median follow-up of 55 months • Primary end point – DFS • Secondary end point – OS . Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol. 2002;21:36a. 2002,2013
  40. 40. • TAC resulted in • 28 % reduction in the risk of relapse (P=0.001) • 30 % decrease in the risk of death (P=0.008) • significant improvement in 5yr DFS& OS
  41. 41. Lancet Oncol. 2013 Jan;14. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of BCIRG 001 trial Median follow-up of 124 months RESULTS disease-free survival was 62% (95% CI 58–65) TAC group and 55% (51–59) FAC group (hazard ratio [HR] 0·80, 95% CI 0·68–0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72–79) TAC group and 69% (65–72) FAC group (HR 0·74, 0·61– 0·90; log-rank p=0·0020) TOXICITY  Grade 3–4 heart failure occurred in 26 (3%) TAC group and 17 (2%) FAC group, .A substantial decrease in LVEF (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) TAC and 41 (15%) FAC. Six patients in TAC developed leukaemia or myelodysplasia, as did three patients who received FAC.
  42. 42. • PACS 01 FNCLCC • Pts – 1999 (996-FEC & 1003-FEC-D) • Operable, node-positive, breast cancer • Primary end point - OS • Secondary end point – DFS • Median follow up – 60 mnths Between June 1997 and March 2000, 1,999 patients with operable node-positive breast cancer FEC every 21 days for 6 cycles or 3 cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006;24:5664–71.
  43. 43. • TOXICITY • Incidence of grade 3 -4neutropenia, need for G-CSF, and incidence of nausea/vomiting were higher with FEC×6 • Docetaxel associated with more febrile neutropenia in fourth cycle, stomatitis, edema, and nail disorders. • there were fewer cardiac events after FEC-D (P .03), attributable mainly to the lower anthracycline cumulative dose • CONCLUSION • FEC-D significantly improves DFS & OS in node-positive breast cancer patients and has a favorable safety profile FEC FEC-D P 5-yr DFS 73.2% 78.4% 0.011 5-yr OS 86.7% 90.7% 0.014 18% reduction in the relative risk of relapse & 27% reduction in the relative risk of death with FEC-D.
  44. 44. Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow- up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27:1177–83. Rationale: • TC active in MBC, devoid of cardiotoxicity, different toxicity profile compared to AC • June 1997 and December 1999, • 1,016 patients, stage I -III operable invasive breast cancer • Primary end point – DFS • Secondary end pint – OS US Oncology Research Trial 9735
  45. 45. 7-Year FU of US Oncology Trial 9735 • At a median of 7 years follow-up, TC AC P DFS 81% 75% 0.033 OS 87% 82% 0.032
  46. 46. • TC was superior in older as well as younger patients. • TC was equally effective in hormone receptor–positive e as well as -negative disease • Older women experienced more febrile neutropenia with TC and more anaemia with AC. CONCLUSION:With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in low risk and intermediate risk both older and younger patients
  47. 47. • Node positive , • stage II-IIIA • 2,005 female • 2 X 2 Factorial design • Primary end point – DFS • Secondary end pint – OS • Median follow up – 36 months Evidence for dose dense chemotherapy Citron M, et al. J Clin Oncol. 2003;21:1431-1439. sequential A × 4 (doses) → T × 4 → C × 4 concurrent AC × 4 → T × 4
  48. 48. Citron M, et al. J Clin Oncol. 2003;21:1431-1439. •Four-year DFS was 82% for the dose-dense regimens and 75% for the others. •There was no difference in either DFS or OS between the concurrent and sequential schedules. •There was no interaction between density and sequence
  49. 49. • TOXICITY • 3WEEKLY vs DOSE DENSE REGIMEN • Severe neutropenia was less frequent in dose dense regimens likely due to filgrastim • Grade 4 granulocytopenia (< 500/μL) was more frequent on the 3-week regimens compared with the dose-dense regimens (33% v 6%; P < .0001). • SEQUENTIAL vs CONCURRENT • Severe neurotoxicity was rare overall but more frequent in the concurrent chemotherapy than in the sequential regimens (4% v 2%; P = .0050). • Grade 3 or greater emesis was significantly more common for the concurrent regimens than for the sequential regimens (7% v 3%; P = .0002) • Dose-dense chemotherapy significantly reduced contralateral breast cancer (0.3% v 1.5%; P = .0004). • CONCLUSION • The DFS and OS advantages of dose density were not accompanied by an increase in toxicity Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
  50. 50. • ECOG 1199 • 4950 women • Axillary lymph node–positive • or high-risk (tumor stage T2- T3 N0) • Primary end point – DFS • Secondary end pint – OS • Median follow up – 63.8 mtnhs Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663–71.
  51. 51. Toxicity profile GRADE 3-4 TOXICITY •30% paclitaxel every 3 weeks (control) •28% in paclitaxel weekly (P = 0.32), •71% docetaxel every 3 weeks (P<0.001), •45% docetaxel weekly (P<0.001). group receiving weekly paclitaxel had a significantly higher incidence of grade 2, 3, or 4 neuropathy (27%) than any of the other treatment groups (P<0.001for each comparison). higher proportions of grades 3 and 4 toxic effects in group receiving docetaxel every 3 weeks were due to a 46% incidence of neutropenia( ≤4% for the other groups), which resulted in higher rates of febrile neutropenia (16%) and infection (13%) than in the other groups (1% and ≤4%,respectively, for all other groups)
  52. 52. EBCTCG Overview 2005 Early Breast Cancer Trialists’Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717. • Randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. • Many trials involved CMF , Anthracycline-based combinations such as FAC or FEC tamoxifen, or ovarian suppression • None involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors.
  53. 53. Benefits of polychemotherapy vs no chemotherapy Cohort Rates of recurrence with and without chemotherapy (%) Absolute benefit (%) Age < 50 yr, LN- 17.5 vs 27.4 9.9 Age < 50 yr, LN+ 40.6 vs 55.2 14.6 Age 50-69 yr, LN- 14.3 vs 19.6 5.3 Age 50-69 yr, LN+ 36.7 vs 42.6 5.9
  54. 54. Anthracyclines vs. CMF • Anthracycline-containing polychemotherapy produced greater beneficial effects on recurrence and breast cancer mortality than CMF • Benefit varies according to age • reduces the annual breast cancer death rate by about 38% for < 50 years of age,20% for 50–69 years • largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. The ratio of annual recurrence rates for anthracyclines compared to CMF was 0.89 SE 0.03 (2p=0.001) and the breast cancer death rate ratio was 0.84 SE 0.04 (2p< 0.00001).
  55. 55. EBCTCG 2012 Meta-analysis Early Breast Cancer Trialists’Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432–44.
  56. 56. All randomised trials begun during 1973–2003 of: • polychemotherapy versus no adjuvant chemotherapy • any Anthracycline based regimen versus CMF • higher versus lower Anthracycline dosage • taxane-based versus non-taxane-based regimens
  57. 57. • Trials with CMFshowed that standard 4AC and standard CMF were equivalent (2p=0·67), • but that Anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (e.g. CAF or CEF) were superior to standard CMF (2p=0·0004). Any Anthracycline Based Regimen Versus Standard Or Near-standard CMF Higher Versus Lower Anthracycline Dosage
  58. 58. Taxane-based Versus Non-taxane-based Regimens In trials adding four separate cycles of a Taxane to a fixed Anthracycline-based control regimen Taxane-based (4×AC-4×T)Versus fixed Non-taxane-(4×AC)based Regimens
  59. 59. Taxane-based (4×AC-4×T)Versus More Non-taxane- (6×FEC/FAC)based Regimens
  60. 60. Neo-adjuvant chemotherapy
  61. 61. Benefits of preoperative systemic therapy • Can render inoperable tumors operable • Facilitates breast conservation • Provides important prognostic information based on response to therapy, particularly in patients with triple- negative and HER2-positive breast cancer • Allows time for genetic testing
  62. 62. Candidates of Preoperative systemic therapy • Patients with inoperable breast cancer • Inflammatory breast cancer • Bulky or matted N 2 axillary nodes • N 3 Nodal disease • T 4 disease • Patients with operable breast cancer • Large primary tumour relative to breast size in a patient who desires breast conservation NCCN 2016
  63. 63. Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer :SURVIVAL No Significant Difference In Overall Survival No. of pts Chemo regimen Tumor stage Path CR% Overall survival Neoadjuvant adjuvant Follow-up (yr) NSABP B-18 1523 AC T1-T3 13% 70 69 10.3 EORTC 698 FEC T1c-T4b 4 72 67 9 act ECTO 880 AT CMF T2-T3 20 90 87 4.2 med Institut Curie 414 FAC T2-T3 - 60 65 8.8 Royal Marsden 309 MM(M) T0-T4 13 63 70 9.3 med Bordeaux 272 EVM/MTV T2-T3 - 59 62 10.3 ABCSG-07 398 CMF T1-T3 6 68 64 10 act
  64. 64. Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer :RATES OF BCS
  65. 65. Overview of Randomized Trials Comparing Primary Systemic Therapy and Adjuvant Systemic Therapy in the Breast Cancer :IBTR
  66. 66. • PURPOSE: Tested whether 4 cycle of AC administered preoperatively improved breast cancer DFS and OS • Inclusion: • Primary end point – DFS • Secondary point – Downstaging primary+ AxLN, lumpectomy rates ,Comparisons of IBTR • Results available at median follow up of 5 & 9 years NSABP B-18
  67. 67. Pts with pCR had an OS rate 88.7% which was superior to others (P < 0.0001). 5yr OS survival & response to chemo  Path CR = 87%  Clin PR = 68%  Clin NR = 64% p<0.0001 0 1 2 3 4 5 50 60 70 80 90 100 path CR clin PR clin NR years distantdisease-free survival(%) • RESULTS • At Median follow-up of 5 yr • no significant difference seen in DFS and OS (72.3% VS 73.2%)
  68. 68. •Updated results Survival at 9 years is 70% in the postoperative group and 69% in the preoperative group (P = .80). DFS is 53% in postoperative patients and 55% in preoperative patients (P = .50).
  69. 69. RESULTS • Secondary End Points • Rate Of BCS: Preop chemo resulted in a statistically significant increase in rate of BCTf rom 60% to 68%, particularly notable in tumors >5 cm, in whom BCT was increased from 8% to 22% • IBTR Rates Median f/u of 9.5 yrs IBTR was 8% for ACT arm compared with 11% for NACT arm Although the rate of IBTR was slightly higher in the preoperative group (10.7% versus 7.6%), this difference was not statistically significant
  70. 70. • Breast tumor size reduced in 80% of patients after preop chemotherapy; • 36% had a cCR & 26% with a cCR had a pCR • Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. • Overall, 12% more lumpectomies were performed in the preoperative group in women with tumors > or = 5.1 cm CONCLUSION: • Preoperative therapy reduced size of most breast tumors & decreased incidence of positive nodes. • greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > 5 cm, • Preoperative therapy should be considered for breast tumors judged too large for lumpectomy.
  71. 71. • 2,411 pts. • • T1c-T3, N0-N1, M0 • • Movable in relation to chest wall and skin • • Nodes of any size but not fixed to each other or to adjacent structures Bear JCO 2003 Aim: Tested the role of taxane to AC preoperatively any improvement in DFS or OS. . NSABP-B27
  72. 72. • addition of docetaxel preoperatively resulted in significant increases in cCR and pCR compared with AC alone (65% versus 40.1% and 25.6.% versus 13.7%, respectively
  73. 73. Addition of docetaxel significantly reduced the incidence of local recurrences as first events, including IBTR in patients treated with breast conservation
  74. 74. • No significant difference in DFS or OS There was a trend toward improved DFS in group II patients who received preoperative T, but this was not statistically significant (72% versus 67% DFS at 5 years; HR = 0.86, P = 0.10).
  75. 75. In an analysis of RFS  group II had a significantly better outcome compared with group I (74% versus 69% RFS at 5 years; HR = 0.81, P = 0.04). Group III RFS was not significantly different from group I (71% at 5 years; HR = 0.91, P = 0.32). Pathologic complete response was a highly significant predictor of DFS and OS in all treatment groups HR = 0.45, P < 0.0001 DFS HR = 0.33, P < 0.0001OS
  76. 76. EORTC 10902 JCO November 15, 2001 vol. 19 no. 22 4224-4237 To evaluate whether preoperative neoadjuvant chemotherapy FEC 1. results in better overall survival (OS) and relapse-free survival 2. permits more breast-conserving surgery procedures than postoperative chemotherapy 698 breast cancer patients (T1c-T4b, N0 to 1, and M0) Four cycles of FEC administered preoperatively versus the same regimen administered postoperatively
  77. 77. • median follow-up of 10 years, • there was no statistically significant difference between the two treatment arms for OS, DFS or loco regional recurrences • Preoperative chemotherapy was associated with an increase in BCT rates. • BCT after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT without preop chemo
  78. 78. Cochrane review 2012 Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD005002.  14 eligible studies which randomised a total of 5,500 women.  Women with operable breast cancer: TNM stage T1c, T2, T3,  N0 to 2, and M0 (AJCC stage I-IIIA).  No restrictions to age or menopausal status.  Median follow-up ranged from 18 to 124 months Primary outcomes: - overall survival - disease-free survival - loco-regional recurrence as first event To assess the effectiveness of preoperative chemotherapy in women with operable breast cancer when compared to postoperative chemotherapy.
  79. 79. Overall survival There was no detectable difference between preoperative and postoperative chemotherapy with a HR of 0.98 (95% CI, 0.87 to 1.09; P, 0.67) Comparable overall and disease-free survival rates for preoperative and post-operative chemotherapy, although a higher loco- regional recurrence rate for patients receiving preoperative chemotherapy
  80. 80. • Disease-free survival • Ten studies reported disease-free survival data on 4510 randomised women involving 1596 estimated events. • There was no detectable difference between preoperative and postoperative chemotherapy with a HR of 0.97 (95% CI, 0.89 to 1.07; P, 0.58) and with moderate heterogeneity across studies (I2, 32.5%; P, 0.15)
  81. 81. Time to locoregional recurrence statistically significant difference in favour of postoperative chemotherapy with HR of 1.21 (95%CI, 1.02 to 1.43; P, 0.03)
  82. 82. CONCLUSION • Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast conserving therapy. • Pathologic response rate,, is an important outcome as it is presumably associated with eradication of micrometastatic disease and result in improved outcomes • No detectable difference between preoperative and postoperative chemotherapy with respect to survival • Rate of IBTR was slightly higher in the preoperative group
  83. 83. Metastatic breast cancer
  84. 84. Treatment goal • Palliation of sign and symptoms. • Control of tumor burden. • Maintenance of quality of life and function.
  85. 85. Prognostic Factors in Patients With Metastatic Breast Cancer Prognostic factor Favorable Unfavorable Performance status Good Poor Sites of disease Bone, soft tissue Viscera, CNS No. of sites of disease Few Multiple Hormone receptor status Positive Negative Her-2/neu status Negative Positive (significance less clear in Her-2/neu inhibitors era) Disease-free interval >2 years <2 years
  86. 86. Systemic Treatment Approach for Metastatic Breast Cancer Metastatic Breast Cancer • Limited metastases (bone & soft tissue) • Positive hormone receptors • Disease-free interval 2 years • Extensive disease or visceral crisis • Negative hormone receptors • No response to hormones Hormonal Therapy Chemotherapy Response No response No progression Progression of disease If disease progresses, second-line hormonal therapy Second-line chemotherapy
  87. 87. Choice of chemotherapy single agent sequential treatment vs combination treatment with multiple agent • Randomised studies suggested that combined chemotherapy may be associated with heigher response rates and improved time to progression compared with single agent • However, there are no prospective data that show combination chemotherapy improves overall survival compared with single agent sequential chemotherapy. • higher chance of response with combination chemotherapy should be weighted against higher treatment toxicity,
  88. 88. Single vs Combination chemotherapy • In the Eastern Cooperative Group (ECOG) 1193 trial • 700 women were randomly assigned to doxorubicin plus paclitaxel (AP), doxorubicin, or paclitaxel Treatment with AP resulted in: • A higher overall response rate (ORR) compared with doxorubicin or to paclitaxel (47 versus 36 and 34 percent) • A longer median time to progression (TTP; 8 versus 6 and 6 months) (p value .011) • However, there was no difference in overall survival (OS; 22 versus 19 and 22 months)
  89. 89. Anthracycline pre-treated metastatic breast cancer
  90. 90. Anthracycline & Taxane pre-treated metastatic breast cancer
  91. 91. Combination: capecitabine + Docetaxel Patients were randomized to  21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or  Docetaxel 100 mg/m(2) on day 1 (n = 256).
  92. 92. Capecitabine/docetaxel resulted in significantly superior efficacy in  time to disease progression (TTP)( P =.0001; median, 6.1 v 4.2 months),  overall survival (P =.0126; median, 14.5 v 11.5 months),  objective tumor response rate (42% v 30%, P =.006) compared with docetaxel.
  93. 93. Combination: Capecitabine + Docetaxel vs Gemcitabine + docetaxel  Patients were randomly assigned to  GD (G 1,000 mg/m2 days 1 and 8; D 75 mg/m2 day 1) or  CD (C 1,250 mg/m2 twice daily days 1 through 14; D 75 mg/m2 day 1) every 21 days.  Comparison of progression-free survival (PFS) was the primary objective. J Clin Oncol 27:1753-1760. © 2009
  94. 94.  No difference was observed between GD and CD arms in PFS, ORR, and OS.  TTF was longer in the GD arm.  nonhematologic toxicity profile that favors GD over approved doses of CD,  suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this clinical setting.
  95. 95. Combination: Ixabepilone + capecitabine Clin Oncol 25:5210-5217. © 2007 752 patients were randomly assigned to  Ixabepilone 40 mg/m2 intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m2 orally on days 1 through 14 of a 21-day cycle, or  capecitabine alone 2,500 mg/m2 on the same schedule, The primary end point was progression-free survival
  96. 96. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P .0003) Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.
  97. 97. THANKYOU

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