Purpose: This study was designed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a standard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival.

Patients and Methods: After surgical treatment, 3,121 women with operable breast cancer and involved lymph nodes were randomly assigned to receive a combination of cyclophosphamide (C), 600 mg/m², with one of three doses of doxorubicin (A), 60, 75, or 90 mg/m², for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m². Tamoxifen was given to 94% of patients with hormone receptor–positive tumors.

Results: There was no evidence of a doxorubicin dose effect. At 5 years, disease-free survival was 69%, 66%, and 67% for patients randomly assigned to 60, 75, and 90 mg/m², respectively. The hazard reductions from adding paclitaxel to CA were 17% for recurrence (adjusted Wald χ² P = .0023; unadjusted Wilcoxon P = .0011) and 18% for death (adjusted P = .0064; unadjusted P = .0098). At 5 years, the disease-free survival (± SE) was 65% (± 1) and 70% (± 1), and overall survival was 77% (± 1) and 80% (± 1) after CA alone or CA plus paclitaxel, respectively. The effects of adding paclitaxel were not significantly different in subsets defined by the protocol, but in an unplanned subset analysis, the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 (95% confidence interval, 0.59 to 0.86) for those with estrogen receptor–negative tumors and only 0.91 (95% confidence interval, 0.78 to 1.07) for patients with estrogen receptor–positive tumors, almost all of whom received adjuvant tamoxifen. The additional toxicity from adding four cycles of paclitaxel was generally modest.

Conclusion: The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer.