No Disease-Free Survival Differences Among Doxorubicin/Cyclophosphamide Plus Paclitaxel Regimens in High-Risk Early-Stage Breast Cancer
In the phase III SWOG S0221 trial reported in the Journal of Clinical Oncology, Budd et al found no differences in disease-free survival among four different doxorubicin/cyclophosphamide plus paclitaxel regimens in patients with node-positive or high-risk node-negative breast cancer. A subgroup analysis suggested benefit of once-every-2-week dosing among patients with hormone receptor–negative/HER2-negative disease.
Study Details
This 2×2 factorial design trial tested two hypotheses: (1) that a novel continuous schedule of doxorubicin/cyclophosphamide was superior to six cycles of doxorubicin/cyclophosphamide once every 2 weeks; and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks.
Between December 2003 and November 2010, 2,716 patients were randomly assigned to doxorubicin/cyclophosphamide every 2 weeks for six cycles plus paclitaxel every 2 weeks for six cycles (n = 678), doxorubicin/cyclophosphamide weekly for 15 weeks plus paclitaxel every 2 weeks for six cycles (n = 693), doxorubicin/cyclophosphamide every 2 weeks for six cycles plus paclitaxel weekly for 12 weeks (n = 697), or doxorubicin/cyclophosphamide weekly for 15 weeks plus paclitaxel weekly for 12 weeks (n = 648). The primary endpoint was disease-free survival.
Futility for Demonstrating Differences
Futility boundaries were crossed for the doxorubicin/cyclophosphamide comparison at the first interim analysis in September 2010. Accrual was suspended in November 2010, and the trial was reopened in December 2010 with all patients assigned to four cycles of every-2-week doxorubicin/cyclophosphamide and randomization to the two paclitaxel schedules (total of 578 additional patients). The futility boundary for the paclitaxel comparison was crossed at the third interim analysis in September 2012.
Median follow-up was 6 years in patients without an event. A significant interaction was observed between the doxorubicin/cyclophosphamide and paclitaxel randomization factors (P = .024 for disease-free survival, P = .010 for overall survival) among patients randomized according to the original design, which precluded separate interpretation of the two randomization factors.
Disease-Free Survival
Comparison of all four groups simultaneously showed no difference in disease-free survival (P = .11). Compared with the every-2-week group, hazard ratios were 1.32 (P = .022) for doxorubicin/cyclophosphamide weekly/paclitaxel every 2 weeks, 1.24 (P = .072) for doxorubicin/cyclophosphamide every 2 weeks/weekly paclitaxel, and 1.12 (P = .38) for the weekly group.
Overall Survival
Comparison of all four groups showed a significant difference in overall survival (P = .040), with the highest overall survival in the every-2-week group; compared with this group, hazard ratios were 1.44 (P = .013) for doxorubicin/cyclophosphamide weekly/paclitaxel every 2 weeks, 1.46 (P = .011 for doxorubicin/cyclophosphamide every 2 weeks/weekly paclitaxel, and 1.24 (P = .17) for the weekly group.
Subset Analysis
Unplanned subset analyses to investigate the possible interaction between the doxorubicin/cyclophosphamide and paclitaxel schedules showed no significant differences by treatment and no interaction between doxorubicin/cyclophosphamide and paclitaxel schedules for hormone receptor–positive tumors and HER2-positive tumors and nonsignificant trends for disease-free survival (P = .077) and overall survival (P = .067) and significant interactions between doxorubicin/cyclophosphamide and paclitaxel schedules (P = .018 for disease-free survival, P = .010 for overall survival) for triple-negative tumors. Overall survival was greatest when both doxorubicin/cyclophosphamide and paclitaxel were given every 2 weeks.
The investigators concluded: “Patients achieved a similar disease-free survival with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.”
George T. Budd, MD, of Taussig Cancer Center, Cleveland Clinic, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the National Cancer Institute, Canadian Cancer Society Research Institute, and Amgen. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
