The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer

To increase the dose-intensity of two drugs in metastatic breast cancer, we tested the feasibility, in phase I studies, of two schedules of epirubicin (E) and cyclophosphamide (C) - sequential (E-->C) and alternating (E/C) - with respect to the standard combination (EC). Drugs were given at three pl anned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (3 0), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treate d. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250 , 90/3000 mg/m(2). In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E-->C schedule, t hree cycles of epirubicin then three cycles of cyclophosphamide were admini stered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m(2) (E) and 2000, 3000, 4000 mg/m(2) (C). The average relative dose-intensity was 1.2-fold and 2-fold greater w ith E/C and E-->C, respectively, than with EC. The third level dose was fea sible with all schedules. Grade 4 leucopenia occurred in 77% of patients. T hrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one per cent of patients on experimental schedules required red blood cell sup port versus 44.4% of patients on EC. At the third level, platelet transfusi ons were more frequent among patients treated with EC (27.8%). Non-haematol ogical toxicity was mild: about 20% of patients experienced grade 3 vomitin g, irrespective of schedule. Only 2 patients had grade 3 mucositis; no pati ent developed heart failure. Fever (61% of patients) and bone pain (55.5% o f patients) were relevant in the GM-CSF treated groups and 12 patients shif ted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete re sponse and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confid ence intervals = 7-31%). Rapidly alternating or sequential cycles of epirub icin and cyclophosphamide with CSF support is a feasible strategy that allo ws a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombo cytopenia with the standard schedule. Overall, this intensified therapy was very active.