Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: Final analysis from INT-0137 (S9313)

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.