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516 (32723) Phase III trial comparing AC (x4)taxane (x4) with taxane (x8) as adjuvant therapy for node-positive breast cancer: Results of N-SAS-BC02 trial (Japan) T. Watanabe, M. Kuranami, K. Inoue, N. Masuda, K. Aogi, H. Iwata, H. Mukai, S. Tanaka, T. Yamaguchi, Y. Ohashi Background • Doxorubicin and cyclophosphamide (AC) x 4 paclitaxel x 4 is a standard regimen for postoperative chemotherapy. • Rare but serious side effects (e.g., cardiac failure, secondary leukemia) are major concerns with AC. • AC cannot be used in some patients. • Relative efficacy of docetaxel to that of paclitaxel needs to be clarified. Trial Design ACP R A N D O M I Z E ADM 60 mg/m2 CPA 600 mg/m2 ACD Paclitaxel 175 mg/m2 PTX Docetaxel 75 mg/m2 DTX Pts with BCS received RT. Pts with ER(+) BC received TAM or an AI for 5 yrs. 0 3 6 9 12 15 weeks 18 21 Primary objectives To compare disease-free survival (DFS) with AC (x4)taxane (x4) vs. taxane (x8) To compare DFS with paclitaxel (x8) vs. docetaxel (x8) in node-positive breast cancer Exploratory analyses To find subsets of patients who benefit from additional treatment with AC Subsets: HER2 positive vs. HER2 negative or unknown ER positive vs. ER negative or unknown Inclusion Criteria • Stage I to IIIA invasive breast cancer • Histologically involved axillary lymph nodes • Age 18-75 years • PS (ECOG) 0, 1 • No prior chemotherapy or endocrine therapy • Adequate organ functions • Written informed consent Statistical Considerations Hypothesis 1: A taxane (x8) is not inferior to AC (x4) a taxane (x4) Hypothesis 2: One of the taxanes is superior or equivalent to the other. Planned N = 1200 (based on planned events (≥320) in hypothesis 1) a=0.05; 1-sided (non-inferiority); power (1-b) = 0.80 Patient accrual • Between December 2001 and April 2006, 1060 patients were randomized at 84 institutions in Japan. • Date of first analysis: June 15, 2008 Patient Disposition Patients randomly assigned (n=1060) ACP 263 ACD 265 PTX 267 DTX 265 Patients eligible for this trial (n=1060) ACP 263 ACD 265 PTX 267 DTX 265 Patients analyzed for safety and efficacy (n=1044) ACP 260 ACD 262 PTX 263 DTX 259 Patients completed protocol therapy (n=902) ACP 227 ACD 226 PTX 228 DTX 221 Did not receive protocol therapy (n=16) ACP 3 ACD 3 PTX 4 DTX 6 Did not complete protocol therapy (n=142) ACP 33 ACD 36 PTX 35 DTX 38 Patient characteristics (1) ACP (n=260) ACD (n=262) PTX (n=263) DTX (n=259) 52.8±8.3 52.7±9.5 52.4±8.7 51.9±8.6 I 42 18 29 35 II A 95 115 102 103 II B 85 106 109 97 III A 38 23 23 24 <3 cm 168 167 167 165 ≥3 cm 92 95 96 94 Age(mean±sd) Stage Pathological tumor size Number of positive lymph nodes 1-3 154 158 156 154 4-9 63 61 64 64 10 - 43 43 43 41 Patient characteristics (2) Estrogen Receptor positive negative not tested Progesterone Receptor positive negative unknown Type of surgery Breast conserving surgery Mastectomy Others HER2 (HercepTest®) 0 1+ 2+ 3+ unknown ACP ACD PTX DTX 147 110 3 144 116 2 147 111 5 144 112 3 107 149 4 122 138 2 109 147 5 113 142 4 121 135 4 121 140 1 122 139 2 121 136 2 85 76 24 35 40 77 68 26 36 55 91 63 29 35 45 90 61 27 34 47 Grade ¾ adverse events (%) (1) Neutropenia Leukopenia Thrombocytopenia Anemia Febrile neutropenia Elevated AST or ALT Elevated bilirubin Edema Pleural effusion Ascites Body weight gain Hair loss Phlebitis (injection site) Nail changes ACP 17 3 0 0 5 2 0 0 0 0 0 0 0 0 ACD 18 5 0 0 11 1 0 1 0 0 0 0 0 0 PTX 2 0 0 0 0 2 0 0 0 0 0 0 0 0 DTX 6 2 0 0 8 0 0 11 0 0 0 0 0 0 Grade ¾ adverse events (%) (2) Stomatitis Nausea Vomiting Constipation Diarrhea Urinary urgency Hematuria Fatigue Lacrimation Rash, desquamation Sensory neuropathy Motor neuropathy Joint pain (arthralgia) Muscle pain (myalgia) ACP ACD PTX DTX 1 5 3 1 0 0 0 3 0 2 4 2 6 4 1 3 3 1 1 0 0 3 0 1 0 1 4 3 0 0 0 0 0 0 0 2 0 0 6 1 8 5 0 1 1 0 2 0 0 2 0 1 4 1 2 1 Disease-free Survival 100 Percent probability 90 80 70 :ACP :ACD :PTX :DTX 60 50 ~ ~ 0 0 1 2 3 Time from randomization (years) 4 Disease-free Survival Summary of events (disease-free survival) No. of pts ACP ACD PTX DTX 258 255 261 257 Hypothesis 1: A taxane alone is not inferior to AC + a taxane Hazard ratio (AC + a taxane as standard) 1.26 99% CI 0.92 - 1.72 90% CI 1.03 - 1.53 p value 0.67 Hypothesis 2: Whether PTX or DTX is more effective Hazard ratio (PTX as standard) 0.81 99.5% CI 0.57 - 1.14 95% CI 0.64 - 1.03 p value 0.08 ・Two confidence intervals are calculated for each endpoint, taking into account multiplicity due to interim analysis. ・Final analysis will be planned number of events (>=320) are observed. Percent probability Disease-free Survival 100 100 90 90 80 80 70 70 60 60 50 ~ ~ : AC –>Taxane : Taxane :ACD+DTX :ACP+PTX 50 Hazard ratio (99%CI):1.26(0.92 – 1.72) ~ ~ Hazard ratio (99.5%CI):0.81(0.57 – 1.14) 0 1 2 3 4 Time from randomization (years) 0 0 0 1 2 3 4 Time from randomization (years) AC Taxane vs. Taxane Subset according to HER2 HER2 positive HER2 negative/unknown 100 90 90 80 80 70 70 60 60 Percent probability 100 50 ~ ~ : AC Taxane : Taxane : AC Taxane : Taxane 50 ~ ~ Hazard ratio (95% CI): 1.63(1.05 – 2.54) 0 Hazard ratio (95% CI): 1.13(0.85 – 1.50) 0 0 1 2 3 Time from randomization(years) 4 0 1 2 3 4 Time from randomization (years) ・Interactions between the response to AC and HER-2 positive/HER-2 negative/unknown status, P=0.17 AC Taxane vs. Taxane Subset according to ER ER negative Percent probability ER positive 100 100 90 90 80 80 70 70 60 60 :AC Taxane :Taxane 50 ~ 50 ~ ~ Hazard ratio (95%CI):1.32(0.90 – 1.95) :AC Taxane :Taxane Hazard ratio (95%CI):1.22(0.90 – 1.66) 0 0 0 1 2 3 4 Time from randomization (years) 0 1 2 3 4 Time from randomization (years) Summary (1) • Taxane (x8) is not demonstrated to be non-inferior to AC (x4) a taxane (x4) in the study group as a whole in terms of DFS. • Docetaxel (75 mg/m2) is superior to paclitaxel (175 mg/m2) when given every 3 weeks in terms of DFS. • In the subset of HER2-positive patients, AC (x4) a taxane (x4) produced superior DFS than did a taxane (x8). This result was not obtained in patients with HER2-negative or unknown tumors. • For ER, there was no interaction with the addition of AC. Summary (2) • Regarding the incidences of adverse events: –Nausea and vomiting were higher with AC (x4) a taxane (x4) than with taxane (x8) . –Edema and febrile neutropenia were higher with docetaxel (75 mg/m2) than with paclitaxel (175 mg/m2) . –Sensory neuropathy was higher with paclitaxel (175 mg/m2) than with docetaxel (75 mg/m2) . Conclusions • AC can be omitted in certain subsets of patients with postoperative breast cancer. • When given every 3 weeks, docetaxel (75 mg/m2) improves DFS in women with node-positive breast cancer as compared with paclitaxel (175 mg/m2) . • The expression of HER2 may be associated with a benefit from the addition of AC.