Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance)

Abstract

Purpose: Optimal adjuvant chemotherapy for early-stage breast cancer balances efficacy and toxicity. We sought to determine whether single-agent paclitaxel (T) was inferior to doxorubicin and cyclophosphamide (AC), when each was administered for four or six cycles of therapy, and whether it offered less toxicity.

Patients and methods: Patients with operable breast cancer with 0 to 3 positive nodes were enrolled onto the study to address the noninferiority of single-agent T to AC, defined as the one-sided 95% upper-bound CI (UCB) of hazard ratio (HR) of T versus AC less than 1.30 for the primary end point of relapse-free survival (RFS). As a 2 × 2 factorial design, duration of therapy was also addressed and was previously reported.

Results: With 3,871 patients enrolled onto the trial, a median follow-up period of 6.1 years, and 437 RFS events, we achieved an HR of 1.26 (one sided 95% UCB, 1.48; favoring AC does not allow a conclusion of noninferiority of T with AC; UCB > 1.3). With 266 patient deaths, the HR for overall survival (OS) was 1.27 favoring AC (UCB, 1.56). The estimated absolute advantage of AC at 5 years is 3% for RFS (91 v 88%) and 1% for OS (95 v 94%). All nine treatment-related deaths were patients receiving AC and are included in the analyses of both RFS and OS. Hematologic toxicity was more common in patients treated with AC, and neuropathy was more common in patients treated with T.

Conclusion: This trial did not show noninferiority of T to AC, a conclusion that is unlikely to change with additional events and follow-up. T was less toxic than AC.

Trial registration: ClinicalTrials.gov NCT00041119.

Fig 1.

CONSORT diagram. Randomized controlled trial: patients registered, treatment-arm assignments, and exclusions. Cyclophosphamide and doxorubicin (AC) was administered as noted as doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² given every 2 or 3 weeks for four or six cycles. T (paclitaxel) was administered as 80 mg/m² when given weekly for 12 or 18 weeks (3 weeks equaling one cycle) or as 175 mg/m² when administered every 2 weeks for four to six cycles.

Fig 2.

(A) relapse-free survival (RFS) for all patients (hazard ratio [HR] 1.26; 95% CI, 1.05 to 1.53) favoring doxorubicin and cyclophosphamide (AC); (B) overall survival (OS) for all patients (HR 1.27; 95% CI, 1.00 to 1.62) favoring AC; (C) RFS for hormone receptor–positive tumors; (D) RFS for hormone receptor–negative tumors. T, paclitaxel; yr, year.

Fig 3.

Relapse-free survival by treatment arm. Doxorubicin and cyclophosphamide (AC) was administered as noted as doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² given every 2 or 3 weeks for four or six cycles. Paclitaxel (T) was administered as 80 mg/m² when given weekly for 12 or 18 weeks (3 weeks equaling one cycle) or as 175 mg/m² when administered every 2 weeks for four or six cycles.