8. Evolution of Chemotherapy :
• CMF (6 vs 12)
• FAC/FEC & TAC(6)
• 4AC
• Addition of Taxanes (3/4AC->T)
• Dose dense schedules of Paclitaxel (weekly and two-weekly)
Progress in adjuvant chemotherapy for breast cancer: an overview ; JesusAnampa*, Della Makower and JosephA. Sparano et al. BMC Medicine (2015) 13:195
9. Trial Year Control arm Treatment arm FU (yr) DFS/RFS OS
24% vs 47% ( p=S)
Surgery alone M F 16 63% vs 77%(p=S)
CMF X 6 ± tam AC X 4 ± tam 8 85% vs 85%(p=NS)
CMF CEF 10 45% vs 52%(p=S)
Bonadonna et al
(N-/+)
NSABP B-13 (N-)
NSABP B-19 (N-)
NSABP B-23 (N-)
NCIC MA5 (N+)
FASG 05(N+)
CALGB 9344(N+) AC dose escalated AC Taxol 5 65% vs 70%(p=S)
65% vs 74%(p=S)
74% vs 82%(p=NS)
85% vs 86%(p=NS)
58% vs 62(p=NS%)
50% VS 55%(p=S)
77% vs 80%(p=S)
NSABP B-28(N+)
CALGB 9741(N+)
2005 AC
2003 AC T or AC T or 4 75% vs 82% (p=S)
A T C q 3 wk A T C q 2wk
85% vs 85%%(p=NS)
90% vs 92%(p=S)
BCIRG 001(N+) 2005 FAC X 6
PACS 01(N+) 2006 FEC X 6
TAC X 6 4.5
FEC X 3 D X 3 5
68% vs 75%(p=S)
73% vs 78%(p=S)
81% vs 87%(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
1976 Surgery alone CMF X 12 20 26% vs 37% (p=S)
2005
1996
1996 M -> F CMF 13 73% vs 83%(p=S)
2001
Better results with anthracycline based chemotherapy
2005
2001 FEC-50 FEC-100 9.2 45% VS 51%(p=S)
2003
Establish superiority of sequential taxol based combination
AC Taxol 5.4 76% vs 72%%(p=S)
Dose dense chemotherapy as a alternative strategy
Evaluate the efficacy of adjuvant Docetaxel
10. 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, MoliterniA,, et al. 30 years’follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ. 2005;330:217.
11. 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
MultivariateAnalyses
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.
12. 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).
CMF 12 cycles Equivalent To CMF 6 Cycles.
OS ( P = 0.04).
RFS ( P = 0.005)
RESULTS
13. 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
14. 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 usinglife-
table estimates.
15. RESULTS
NSABP
B-13
Sx alone Sx + M-->F Pvalue
DFS 59% 74% <0.001
≤49yrs 56% 69% .006
≥50yrs 63% 81% .002
•NSABP B-13 at 8 years follow up
NSABPB-19 M-->F CMF Pvalue
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
16. CMF ESTABLISHED AS GOLD STANDARD FOR
ADJUVANT CHEMOTHERAPY IN EARLYSTAGE BREAST
CANCER TILL1970s
17. 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.
18. 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.
19. 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
20. FASG 05:2001,2005
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 surgeryto
• 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
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.
21. 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
22. Trial Year Control arm FU (yr) DFS/RFS OS
CALGB 9344 2003 5 65% vs 70%(p=S) 77% vs 80%(p=S)
NSABP B-28 2005
AC dose
escalated
AC
Treatment arm
AC Taxol
AC Taxol 5.4 76% vs 72%%(p=S) 85% vs 85%%(p=NS)
ROLE OF TAXANES: PACLITAXEL
23. • 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
24. 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 generallymodest
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.
25. • Between August 1995 and May 1998, 3,060 patients resected operable breast cancerand
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.
Addition of PTX to AC significant improved DFS but no significant
improvement in OS with acceptable toxicity
27. • 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
28. Lancet Oncol. 2013 Jan;14.
Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive
breast cancer: 10-year follow-up of BCIRG 001trial
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-rankp=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.
29. • 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
30. 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
31. • TOXICITY
• 3WEEKLY vs DOSE DENSE REGIMEN
• Severe neutropenia was less frequent in dose dense regimens likely due tofilgrastim
• Grade 4 granulocytopenia (< 500/μL) was more frequent on the 3-week regimens comparedwith
the dose-dense regimens (33% v 6%; P < .0001).
• SEQUENTIAL vs CONCURRENT
• Severe neurotoxicity was rare overall but more frequent in the concurrent chemotherapy thanin
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 intoxicity
Citron M, et al. J Clin Oncol. 2003;21:1431-1439.
32. 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.
33. 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
34. • Trials with CMFshowed that standard 4AC and standard CMF were equivalent(2p=0·67),
• but that Anthracycline-based regimens with substantially higher cumulative dosage thanstandard
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 AnthracyclineDosage
35. Taxane-based Versus Non-taxane-based Regimens
In trials adding four separate cycles of a Taxane to a fixed Anthracycline-based controlregimen
Taxane-based (4×AC-4×T)Versus fixed Non-taxane-(4×AC)based Regimens
38. 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
39. Candidates of Preoperative systemic therapy
• Patients with inoperable breast cancer
• Inflammatory breast cancer
• Bulky or matted N2 axillary nodes
• N3 Nodal disease
• T4 disease
• Patients with operable breast cancer
• Large primary tumour relative to breast size in a patient who desires breast
conservation
NCCN 2016
40. 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 Chemo Tumor Path CR% Overall survival
pts regimen stage 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
41. • PURPOSE: Tested whether 4 cycle of AC administered preoperatively improved breast cancer DFS andOS
• Inclusion:
• Primary end point – DFS
• Secondary point – Downstaging primary + AxLN, lumpectomy rates ,Comparisons ofIBTR
• Results available at median follow up of 5 & 9 years
NSABP B-18
42. 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
100
90
80
70
path CR
clin NR
clin PR
years
distant
disease-free
survival
(%)
• RESULTS
• At Median follow-up of 5 yr
• no significant difference seen in DFS and
OS (72.3% VS 73.2%)
43. •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).
44. 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
45. Bear JCO 2003
Aim: Tested the role of taxane to AC preoperatively any improvement in DFS or OS.
.
• 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
NSABP-B27
46. • 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
47. • 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).
48. 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
49. 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-freesurvival
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
50. • 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
51. 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.
52. 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
53. • 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)
55. 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