First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early breast cancer.
1004 Background: AC+G (doxorubicin 24 mg/m2/week x 15, cyclophosphamide 60 mg/m2/day po, and filgrastim daily except on the days of doxorubicin administration) produced encouraging results in a SWOG Phase II trial of pre-operative chemotherapy in locally advanced breast cancer. S0221 is a SWOG-coordinated Phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer, which hypothesized that the AC+G regimen is superior to ddAC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 IV and pegfilgrastim q 2 weeks x 6) and that weekly paclitaxel is superior to q 2 week paclitaxel. METHODS Between December 2003 and November 2010, 2716 patients were randomized in a 2x2 factorial design to 1) AC+G vs ddAC and 2) paclitaxel 80 mg/m2/week x 12 vs paclitaxel 175 mg/m2 q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. RESULTS By September 8, 2010, 349 events (161 ddAC, 188 AC+G) had occurred among 2,477 patients with follow-up, prompting the first planned interim analysis at 30% of the expected events. The arms were balanced for standard prognostic factors, and a Cox model adjusting for the paclitaxel arms had a HR = 1.21 (95% CI 0.98-1.50; p=0.071) favoring ddAC. The prescribed boundary for futility was the 99.5% CI (0.90-1.64) excluding the original alternative hypothesis that HR=0.82. No boundary was crossed for the paclitaxel comparison and there was no significant interaction of the two factors. Therefore, the Data Safety and Monitoring Committee recommended stopping randomization to the AC+G arms due to futility. Analyses by nodal-, hormone-receptor-, and HER2 status found no subset in which AC+G appeared superior. S0221 has re-opened and randomizes patients to the two paclitaxel arms after only 4 cycles of ddAC. CONCLUSIONS Accrual will continue to 3,250 patients and ancillary studies remain ongoing. We conclude that AC+G is not superior to ddAC x 6, and do not recommend AC+G for routine use. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc.