Sequenced Compared With Simultaneous Anthracycline And Cyclophosphamide In High-Risk Stage I And Ii Breast Cancer: Final Analysis From Int-0137 (S9313)

PurposeWe 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 MethodsHigh-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m(2) and cyclophosphamide 1.2 g/m(2) intravenously (IV) every 3 weeks for six cycles; or ( arm II) in sequence ( A --> C) doxorubicin 40.5 mg/m(2) IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m(2) 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.ResultsBetween 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.ConclusionThe 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.