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

1. Chemotherapy in Breast Cancer
Presented By: Dr. Isha Jaiswal
Moderator: Dr. Neeraj Rastogi
Date: 20th February 2017

2. • Chemotherapy in primary breast cancer
• Adjuvant chemotherapy
• Neo-adjuvant chemotherapy

3. Introduction
• Breast cancer is a systemic disease
• Chemotherapy is an integral part of breast cancer treatment

4. Adjuvant chemotherapy

5. RATIONALE FOR ADJUVANT CHEMOTHERAPY
• Fisher hypothesis
• Gompertzian model

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. CMF ESTABLISHED AS GOLD STANDARD FOR
ADJUVANT CHEMOTHERAPY IN EARLY STAGE
BREAST CANCER TILL 1970s

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. 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. 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. 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. • 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. 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. 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.  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. 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. 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. Improvement in 5 year DFS & OS was significant especially
in patients with more than three positive nodes

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. 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. 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. 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. • 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. No evidence of a doxorubicin dose effect beyond 60 mg/m2/dose

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. • 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.  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. ADDITION OF DOCETAXEL

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. • 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. 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. • 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. • 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. 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. 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. • 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. • 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. 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. • 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. • 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.

52. 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)

53. 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.

54. 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

55. 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).

56. 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.

57. 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

58. • 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

59. 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

60. Taxane-based (4×AC-4×T)Versus More Non-taxane-
(6×FEC/FAC)based Regimens

62. Neo-adjuvant chemotherapy

63. 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

64. 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

65. 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

66. Overview of Randomized Trials Comparing Primary Systemic Therapy and
Adjuvant Systemic Therapy in the Breast Cancer :RATES OF BCS

67. Overview of Randomized Trials Comparing Primary Systemic Therapy and
Adjuvant Systemic Therapy in the Breast Cancer :IBTR

68. • 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

69. 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%)

70. •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).

71. 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

72. • 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.

73. • 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

74. • 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

75. Addition of docetaxel significantly reduced the incidence of local recurrences as first
events, including IBTR in patients treated with breast conservation

76. • 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).

77. 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

78. 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

79. • 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

80. 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.

81. 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

82. • 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)

83. 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)

84. 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

85. Metastatic breast cancer

86. Treatment goal
• Palliation of sign and symptoms.
• Control of tumor burden.
• Maintenance of quality of life and function.

87. 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

88. 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

89. 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,

90. 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)

91. Anthracycline pre-treated metastatic breast cancer

92. Anthracycline & Taxane pre-treated metastatic breast
cancer

93. 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).

94. 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.

95. 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

96.  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.

97. 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

98. 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.

99. THANKYOU