Breast cancer-adjuvant therapy with paclitaxel

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 < 40mg/m2 are Inferior to 60 mg/m2 (CALGB 8541) • Cyclophosphamide 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 < 1 in all stratified subgroups Nodal status (HR: 0.612; P < .001 Menopausal status (HR: 0.603; P < .001) •Multivariate Cox model adjusted for nodal status, age, tumor size, histology, ER and PgR status, Tamoxifen use •HR: 0.632 (P = .001) in favor of FEC plus Paclitaxel Main Findings • Exploratory subgroup analysis (nodal status, menopausal status, ER and PgR status, HER2 status) • FEC plus Paclitaxel better (on average) in all subgroups (some not statistically significant) • Overall survival at 46 months median follow-up • FEC plus Paclitaxel: 94% (34 events) • FEC: 92% (49 events) • P = .1391 Stage II Breast Cancer with 4 Involved Axillary Lymph Nodes Doxorubicin CMF Bonadonna et al., JAMA, 1995 Stage II Breast Cancer with >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 <40 40ﾐ49 50ﾐ59 60+ Nodal Status N0 1ﾐ3 4ﾐ9 10+ ER- and/or PgR-positive Tumor ｲ2 cm 85 6 9 17 34 34 15 11 47 27 15 54 34 AC > 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