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Burdens and Benefits of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil and Tamoxifen for Elderly Patients With Breast Cancer: The International Breast Cancer Study Group Trial VII

From the Centro di Riferimento Oncologico, Aviano; Ospedali Civili and Fondazione Beretta, Brescia; and European Institute of Oncology, Milan, Italy; International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation; and Harvard School of Public Health, Boston, MA; International Breast Cancer Study Group Coordinating Center; and Swiss Group for Clinical Cancer Research, Inselspital, Bern; Kantonsspital; Bürgerspital; and Center for Tumordetection and Prevention, St Gallen; Swiss Group for Clinical Cancer Research, Ospedale San Giovanni, Bellinzona; and Ospedale Civico, Lugano, Switzerland; West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg, Sweden; Australian Cancer Society and University of Sydney, Sydney; Anti-Cancer Council of Victoria, Melbourne; and University of Newcastle, Waratah, Australia; Institute of Oncology, Ljubljana, Slovenia; Groote Schuur Hospital, Cape Town, South Africa; and Madrid Breast Cancer Group, Madrid, Spain.

Address reprint requests to Diana Crivellari, MD, Centro di Riferimento Oncologico Aviano, via Pedemontana Occidentale, 12, Aviano, Italy; email sfrustaci{at}ets.it

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII.

PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m² orally days 1 to 14), methotrexate (40 mg/m² intravenous days 1 and 8), and fluorouracil (600 mg/m² intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years.

RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P = .004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P = .0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P = .99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P = .008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received.

CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.

Initial support provided by the Ludwig Institute for Cancer Research, the Cancer League of Ticino, and the Swiss Cancer League. We further acknowledge the continuing support for central coordination, data management, and statistics provided by the Swedish Cancer League, Australian Cancer Society, Sydney, Australia; Australian-New Zealand Breast Cancer Trials Group (National Health and Medical Research Council grant nos. 880513 and 910420), the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, Bern, Switzerland; the United States National Cancer Institute (grant nos. CA-06516 and CA-75362), Bethesda, MD; and the American-Italian Cancer Foundation (grant no. 101-98).

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