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Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313)

Hannah M. Linden, Charles M. Haskell, Stephanie J. Green, C. Kent Osborne, George W. Sledge, Jr, Charles L. Shapiro, James N. Ingle, Danika Lew, Laura F. Hutchins, Robert B. Livingston, Silvana Martino

From the Puget Sound Oncology Consortium; Southwest Oncology Group Statistical Center, Seattle, WA; University of California School of Medicine, Los Angeles, CA; Baylor College of Medicine, Houston, TX; Indiana University Medical Center, Indianapolis, IN; Dana-Farber Cancer Institute, Boston, MA; Mayo Clinic, Rochester, MN; University of Arkansas for Medical Science, Little Rock, AR; and the Angeles Clinic and Research Institute, Santa Monica, CA

Address reprint requests to Southwest Oncology Group (SWOG-9313) Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

PURPOSE: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).

PATIENTS AND METHODS: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m² and cyclophosphamide 1.2 g/m² intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m² IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m² IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.

RESULTS: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor–positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A C. Grade 4 hematologic toxicity was greater on A C, but nonhematological grade 4 was similar.

CONCLUSION: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

Supported in part by the US Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA49883, CA21115, CA25224, CA31946, CA32291, CA37981, CA35431, CA45377, CA58416, CA22433, CA58686, CA46113, CA04919, CA46441, CA58861, CA46282, CA35261, CA27057, CA76132, CA35192, CA76447, CA76462, CA45450, CA76429, CA63845, CA12644, CA20319, CA63844, CA45560, CA58415, CA14028, CA58658, CA42777, CA35119, CA35090, CA35117, CA13612, CA16385, CA67575, CA68183, CA46368, CA04920, CA74647, and CA52654.

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

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