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Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node-Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102

From the University of Arkansas for Medical Sciences, Little Rock, AR; Southwest Oncology Group Statistical Center; Puget Sound Oncology Consortium, Seattle, WA; University of Texas Health Science Center, San Antonio; Baylor College of Medicine, Houston, TX; Johns Hopkins Medical Center, Baltimore, MD; Missouri Baptist Medical Center, St Louis, MO; and John Wayne Cancer Institute, Santa Monica, CA

Address reprint requests to Southwest Oncology Group (Protocol #8897) 14890 Omicron Drive, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

PURPOSE: We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status.

PATIENTS AND METHODS: Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated.

RESULTS: Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAM v TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05).

CONCLUSION: CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.

Supported in part by the following PHS Cooperative Agreement Grants No. awarded by the National Cancer Institute, Department of Health and Human Services: CA36926, CA32102, CA37981, CA22433, CA20319, CA16116, CA04920, CA35431, CA76447, CA45660, CA12644, CA14028, CA58416, CA35281, CA13612, CA04919, CA35090, CA35176, CA58686, CA58861, CA45466, CA46113, CA58882, CA32734, CA46282, CA35128, CA27057, CA28862, CA46136, CA45450, CA35261, CA35192, CA12213, CA16385, CA58348, CA58658, CA46441, CA58723, CA76462, CA45377, CA35119, CA42777, CA58415, CA52420, CA35178, CA52757, CA52654, CA52650, CA35200, CA03096, CA35262, CA35996, CA35117, CA35084, CA52623, CA76429.

Presented at the 34th Annual Meeting of the American Society of Clinical Oncology, May 16-19, 1998, Los Angeles, CA.

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

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