Breast Cancer-Adjuvant Therapy with Paclitaxel
Breast Cancer…Not a Single Disease
Breast Cancer Treatment Plan
• Lymph Node Status
• Responsiveness to Endocrine Therapy • Other Risk Factors
Adjuvant Chemotherapy of Primary Breast cancer So far…..
• Chemotherapy Improves Disease-Free and Overall Survival
• Polychemotherapy better than Single Agent therapy
• Multiple Cycles provide better results than Single Exposure
• No Major Advantage to Durations more than 3 Months
• Anthracycline Combinations provide better results than CMF
Adjuvant Chemotherapy of PBC-So Far…. • Adriamycin Doses 600 mg/m2 are not Superior (NSABP B-22) • Chemotherapy Seems More Effective in ERThan ER+ Disease (EBCTCG)
Adjuvant Chemotherapy of PBC-Paclitaxel
• Active as First Chemotherapy for Stage IV: 5259% Response Rates (M.D. Anderson, MSKCC et al.) • Active after Extensive Prior Chemotherapy, Including Anthracycline-Resistant Disease: 22-30% Response Rates (NCI, MSKCC et al.)
6 Cycles FEC vs 4 Cycles FEC Plus Weekly Paclitaxel for Adjuvant Therapy of Node-Positive Early Breast Cancer GEICAM Multicenter Randomized Trial 9906
Martin M, Rodriguez-Lescure A, Ruiz A, et al.
Baseline characteristics
Characteristic FEC, 6 Cycles (n = 634) FEC, 4 Cycles Plus Paclitaxel (n = 634)
Median age, yrs
50
50
Premenopausal, %
54
55
Tamoxifen for ER-negative or PgR-positive disease, %
76
82
Mastectomy, %
59
58
Radiotherapy, %
70
71
•Primary endpoint: disease-free survival •Secondary endpoints •Overall survival •Toxicity •Pathologic and molecular markers
Main Findings
•DFS at 46 months median follow-up •FEC plus Paclitaxel: 85% (83 events) •FEC: 79% (128 events) •Hazard ratio (HR): 0.63 (P = .0006) •Confirmatory analysis of DFS HR significantly 4 Involved Axillary Lymph Nodes
60
% at 10 Years
50 40 30 20 10 0 A-CMF CMF/A Relapse-Free Survival Overall Survival
p = .002
Bonadonna et al., JAMA, 1995
CALGB 9141 (Pilot)
Node-Positive Stage II-IIIA (N=172)
Cyclophosphamide 2000 mg/m2 + G-CSF
75 mg/m2
Paclitaxel 175 mg/m2
130/145 (89.7%)of Patients Starting Paclitaxel Completed Rx. On Paclitaxel: 25% Grade IV Leukopenia 4% Grade IV Thrombocytopenia
Demetri et al., ASCO-1997
Intergroup 0148/CALGB 9344
Node-Positive Stage II-IIIA
Cyclophosphamide 600 mg/m2
60
Paclitaxel 175 mg/m2
75 90
G-CSF
No Further Chemotherapy
Relationship of CALGB 9344 (Int 0148) to Current U.S. Cooperative Group Trials
NSABP B-28
Node-Positive Stage II-IIIA
Paclitaxel 225 mg/m2 Cyclophosphamide 600 mg/m2 (Survival) 60 mg/m2 No Further Chemotherapy
Concomitant Tamoxifen x 5 Years for HR(+) or Postmenopausal (Age 50)
Intergroup/CALGB 9741
Node-Positive Stage II-IIIA
3-Week Cycles 2-Week Cycles (w/ G-CSF)
Doxorubicin (A) 60 mg/m2 Paclitaxel (T) 175 mg/m2 Cyclophosphamide (C) 600 mg/m2
Intergroup/SWOG 4-9 LN+ Trial
A
Randomize
T
C
C A
STAMP I or
STAMP V
Intergroup/ECOG Stage II Trial
HER2 (-)
Paclitaxel
Cyclophosphamide 600 mg/m2
Docetaxel
Tamoxifen if HR(+)
Integrating Trastuzumab to Paclitaxel Based Regimen
Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel +/- Trastuzumab as Adjuvant Treatment for Women with HER-2/neu Over expressing Node (+) or High Risk Node (-) Breast Cancer
Clinical Research Goals
• Evaluate whether Trastuzumab adds to the benefit of adjuvant AC paclitaxel in resected HER-2 (+) breast cancer • Evaluate impact of trastuzumab schedule
– Sequential to paclitaxel – Concurrent with paclitaxel
• Evaluate cardiac safety
AC=doxorubicin & cyclophosphamide
Study Schema
Arm A: AC q3w x 4
R A N D O M I Z E
Paclitaxel qw x 12
Arm B: AC q3w x 4
Paclitaxel qw x 12
Paclitaxel qw x 12 + H qw x 12
H qw x 52
Arm C: AC q3w x 4
H qw x 40
Radiation and/or hormonal therapy as indicated
Perez E et al. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m 2; cyclophosphamide, 600mg/m 2; paclitaxel, 80mg/m 2 q3w=every 3 weeks; qw=weekly
Eligibility
• Resected invasive breast cancer • Node (+) • High risk node (-)
– >1.0 cm if ER (-) or >2.0 cm if ER (+)
• HER-2 (+) by central testing
– Protein overexpression (IHC 3+) – Gene amplification (FISH+)
• Cardiac eligibility
– Normal left ventricular ejection fraction – No prior MI or CHF
ER=estrogen receptor; HER2=human epidermal growth factor 2; IHC=immunohistochemistry; FISH=fluorescence in situ hybridization; MI=myocardial infarction; CHF=congestive heart failure
Clinical Endpoints
• Disease-free survival
– Local/regional/distant recurrence
– Contralateral breast disease (including DCIS*) – Second primary invasive cancers – Death due to any cause
• Overall survival
* DCIS=ductal carcinoma in situ
• Two pairwise comparisons Sequential AC T H Concurrent AC T + H H • Goal
Statistical Plan Addition of H to AC T
vs
Control: AC T Control: AC T
vs
– To detect a 33% increase in median DFS from 6.3 to 8.4 years
• Final analysis
– At 663 events for A vs C comparison – At 789 events for A vs B comparison
T=Paclitaxel; DFS=disease free survival
Statistical Plan Timing of H Initiation
• Pairwise comparison
Sequential AC T H
vs
Concurrent AC T + H H
• Goal
– To detect a 29% increase in median DFS from 7.3 to 9.4 years
• Final analysis
– At 590 events for B vs C comparison
Cardiac Testing
R A N D O M I Z E
Arm A: AC x 4
Paclitaxel
Arm B: AC x 4 Arm C: AC x 4
Paclitaxel Paclitaxel + H
H H
3
6
Time (months)
0 LVEF measurement 9 18–21
No H if symptoms or LVEF ↓ >15% or ↓ to 3300)
• 700 patients on chemotherapy • 2701 patients entered prior to 1/1/2005
– Median follow up: 1.5 years
• Total disease-free survival events
– A and B: 220 (of 789 needed) – B and C: 147 (of 590 needed)
Patient and Tumor Characteristics
AC > T, % (n=979) Race Caucasian African American Other Age T> H, % (n=985) 86 7 7 19 32 32 16 11 47 28 14 55 31 AC > T + H > H, % (n=840) 83 6 11 16 34 32 18 12 50 25 13 55 31
Results Disease-Free Survival
Joint Analysis
Pairwise Comparison Number of events
395
Log rank p-value*
3x10
ﾐ12
HR* (95% CI)
0.48 (0.39-0.60)
A C
AC > T vs AC > T + H > H
*Stratified – nodal status and receptor status
N9831 Analysis
Pairwise Comparison Number of events 220 Log rank p-value* 0.2936 HR* (95% CI) 0.87 (0.67-1.13) 0.64 (0.46-0.91)
A vs AC > T > H B (n=1964)**
AC > T
B vs AC > T + H > H C (n=1682)**
*Stratified – nodal status and receptor status **for patients randomized before 1/1/2005
AC > T > H
137
0.0114
Disease-Free Survival: A vs C
From the Joint Analysis
100 90 80 70 60 % 50 40 30 20 10 0 AC > T + H > H Events=134 AC > T Events=261
Hazard ratio=0.48 Stratified logrank 2P=3x10-12
0
1
2 Years 374 427
3
4
Number of patients followed A 1162 689 C 1217 766
193 238
59 74
Disease-Free Survival: A vs B N9831
100 90 80 70 60 % 50 40 30 20 10 0
AC >T >H Events=103 AC > T Events=117
Hazard ratio=0.87 Stratified logrank 2P=0.2936
0
1
2 Years
353 403
3
4
Number of patients followed A 979 629 B 985 637
168 169
15 20
Disease-Free Survival: B vs C N9831
100 90 80 70 60 % 50 40 30 20 10 0
AC > T + H > H Events=53 AC > T > H Events=84
Hazard ratio=0.64 Stratified logrank 2P=0.0114
0
1
2 Years 285 285
3
4
Number of patients followed B 842 501 C 840 520
162 178
20 17
Overall Survival
Joint Analysis Results
Pairwise Comparison Number of events
154
Log rank p-value*
0.015
HR* (95% CI)
0.67 (0.48-0.93)
A AC > T C vs AC > T + H > H
*Stratified – nodal status and receptor status
N9831 Analysis Results
Pairwise Comparison Number of events
79
Log rank p-value*
0.4752
HR* (95% CI)
0.85 (0.55-1.33)
A B
AC > T vs AC > T > H
B C
AC > T > H vs AC > T + H > H
56
0.2696
0.74 (0.43-1.26)
*Stratified – nodal status and receptor status
Advantages of the approach
• Integrates Paclitaxel
– Active as a Single Agent – Active Post-Anthracycline
• Minimizes Incremental Toxicity • Allows Integration of Biological Therapy
Breast Cancer Treatment…The Future