Adjuvant Paclitaxel Not Equivalent to Doxorubicin/Cyclophosphamide in Breast Cancer With 0 to 3 Positive Axillary Nodes


Key Points

  • Paclitaxel was not equivalent to doxorubicin/cyclophosphamide in relapse-free survival or overall survival as adjuvant therapy in patients with 0 to 3 positive nodes.
  • Paclitaxel was less toxic than doxorubicin/cyclophosphamide.

In the phase III Cancer and Leukemia Group B (CALGB) 40101/Alliance trial reported in the Journal of Clinical Oncology, Shulman et al found that noninferiority of adjuvant single-agent paclitaxel was not established vs doxorubicin/cyclophosphamide for relapse-free survival in women with operable breast cancer with 0 to 3 positive nodes. Paclitaxel was less toxic than doxorubicin/cyclophosphamide.

Study Details

In this 2×2 factorial trial, 3,871 patients were randomly assigned between 2002 and July 2010 to receive four (n = 1,142) or six cycles (n = 789) of doxorubicin/cyclophosphamide or four (n = 1,151) or six cycles (n = 789) of paclitaxel. Doxorubicin was given at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 or 3 weeks. Paclitaxel was given at 80 mg/m2 weekly for 12 or 18 weeks (3 weeks = one cycle) or at 175 mg/m2 when administered every 2 weeks.

The six-cycle groups were closed in February 2008 due to slowing accrual. After 2005, trastuzumab (Herceptin) was permitted for patients with HER2-positive tumors. Noninferiority of single-agent paclitaxel was defined as a one-sided 95% upper-bound confidence interval (CI) of the hazard ratio for paclitaxel vs doxorubicin/cyclophosphamide of < 1.30 for the primary endpoint of relapse-free survival.

Overall, 90% of patients had node-negative disease and 68% had hormone receptor–positive disease. Of the 48% of patients tested for HER2 status, 84% were HER2-negative.

No Equivalence

After median follow-up of 6.1 years, the hazard ratio for relapse-free survival was 1.26 in favor of doxorubicin/cyclophosphamide with a one-sided 95% CI upper bound of 1.48, preventing the conclusion of noninferiority of paclitaxel. The hazard ratio for overall survival was 1.27 in favor of doxorubicin/cyclophosphamide with an upper bound of 1.56.

Five-year relapse-free survival was 91% in the doxorubicin/cyclophosphamide group vs 88% in the paclitaxel group, and 5-year overall survival was 95% vs 94%. Outcome was numerically poorer with paclitaxel irrespective of hazard ratio status. There was no interaction between regimen and treatment duration across all four treatment groups for relapse-free survival, indicating that six cycles was not superior to four cycles for doxorubicin/cyclophosphamide or paclitaxel and that paclitaxel was not equivalent to doxorubicin/cyclophosphamide irrespective of treatment duration.


The frequency of any grade ≥ 3 hematologic toxicity was considerably higher in the doxorubicin/cyclophosphamide four-cycle (29%) and six-cycle groups (38%) vs the paclitaxel groups, including higher rates of neutropenia (26% and 33% vs 3% in both). Neuropathy was the most frequent nonhematologic adverse event and grade ≥ 3 toxicity was more common in the paclitaxel groups than in the doxorubicin/cyclophosphamide groups (< 1% in both vs 6% and 12%). 

All nine treatment-related deaths were in patients receiving doxorubicin/cyclophosphamide and are included in the analyses of relapse-free survival and overall survival. Acute myelogenous leukemia or myelodysplastic syndrome developed in seven patients receiving doxorubicin/cyclophosphamide; all died and death was considered related to treatment in each case.

 The investigators concluded, “This trial did not show noninferiority of [paclitaxel] to [doxorubicin/cyclophosphamide], a conclusion that is unlikely to change with additional events and follow-up. [Paclitaxel] was less toxic than [doxorubicin/cyclophosphamide].”

Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit

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