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Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer

From the Department of Medical Oncology, Istituto Nazionale Tumori, Milano, Italy.

Address reprint requests to Gianni Bonadonna, MD, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy; e-mail: gianni.bonadonna{at}istitutotumori.mi.it

PURPOSE: To assess the clinical relevance of different sequences of doxorubicin (DOX) and cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of disease relapse.

PATIENTS AND METHODS: Two randomized trials were activated in the early 1980s. The first study, in patients with one to three involved nodes, was intended to assess the effectiveness of intravenous (IV) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose DOX (CMFDOX). The second study, in patients with more than three involved nodes, compared four courses of full-dose DOX sequentially followed by eight courses of IV CMF (DOXCMF) versus alternating two courses of the same CMF regimen with one course of DOX (CMF/DOX) for a total of 12 courses.

RESULTS: After a median observation of 210 months, no statistically significant difference was documented in the first study (relapse-free survival hazard rate [HR], 1.06; total survival HR, 1.03). In contrast, the delivery of DOX first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54 to 0.87; P = .0017) and death (HR, 0.74; 95% CI, 0.57 to 0.95; P = .018) compared with the alternating regimen.

CONCLUSION: Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.

Supported in part by Contract N01-CM-07338 with the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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