Randomized phase III trial of adjuvant epicirubicin (E) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF) or CMF followed by E in patients with N- or ≤ 3 N+ rapidly proliferating breast cancer (RPBC)

Abstract

560 Background: Antimetabolites are active in proliferating cells, and the adjuvant schedule CMF is highly effective in RPBC, whereas the sequential administration of doxorubicin (D) and CMF is superior to CMF–>D, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant E followed by CMF is superior to the inverse sequence in RPBC. Methods: Patients with N-, T > 1 cm or ≤ 3 N+ and any T RPBC (defined by thymidine labeling index or grade or S-phase or Ki67/MIB1) were randomized to receive E (100 mg/m2 i.v. d 1, q 21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 4 cycles) (arm A) or CMF followed by E (arm B) or CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 6 cycles) (arm C). Arm C was closed after the EBCTCG 2000 meta-analysis (data not shown). The main endpoint was overall survival (OS), and the study had 80% power to detect a 7% absolute increase in 5-year OS with 400 patients per arm. Results: From November 1997 to December 2004, 1066 patients were enrolled (arms A/B/C: 440/438/188): N- 53%, estrogen receptor positive 63%, grade 3, 77%. At a median follow up of 69 months, 5-year disease-free survival was 80% in both arms (A and B) (p = 0.93, logrank test), with adjusted hazard ratio (AHR) 0.99 (95% CI 0.73–1.33, Cox model), and OS was 91% in arm A and 93% in arm B (p = 0.66, logrank), with AHR 0.88 (95% CI 0.58–1.35, Cox model). Adverse events were similar, apart from a small increase in grade 4 neutropenia in arm B. Conclusions: No relevant differences in clinical outcome were observed with the 2 different sequences. Further subgroup analyses are ongoing to verify the efficacy of each sequence as a function of biomolecular and hormonal profiles. No significant financial relationships to disclose.