dxy

Background: ACG (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 SWOGcoordinated Phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer, which hypothesized that the ACG 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) ACG 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 ACG) 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; p0.071) favoring ddAC. The prescribed boundary for futility was the 99.5% CI (0.90-1.64) excluding the original alternative hypothesis that HR0.82. 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 ACG arms due to futility. Analyses by nodal-, hormone-receptor-, and HER2 status found no subset in which ACG 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 ACG is not superior to ddAC x 6, and do not recommend ACG for routine use. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc