Phase I study of high-dose epirubicin in platinum-pretreated patients withovarian carcinoma

Background: In vitro data demonstrated a dose-response relationship for dox orubicin in ovarian cancer (OC) cell lines. However, this dose-response que stion for doxorubicin was never carefully addressed in OC patients. These d ata and the more favorable toxicity profile of the anthracycline analogue e pirubicin prompted us to study high-dose epirubicin (HDE) in relapsed OC pa tients. Patients and Methods: This phase I study included 19 OC patients wi th measurable or evaluable disease and no more than one prior (cisplatin-co ntaining) chemotherapy regimen. Dose escalation was not allowed in individu al patients. Epirubicin was administered by rapid intravenous infusion (<5 min) once every 3 weeks and studied at the following dose levels: 120, 135, 150, 180 and 200 mg/m(2) (at least 3 patients per dose level). None of the patients received hematopoietic growth factors. We defined the maximum tol erated dose (MTD) as the dose at which we observed WHO grade 4 hematologic toxicity in greater than or equal to 50% and/or WHO grade 3 nonhematologic toxicity in greater than or equal to 30% of the patients. Results:The MTD w as 200 mg/m(2), with DLT being both hematologic (leukopenia and/or thromboc ytopenia) and nonhematologic (mucositis). Objective responses were observed in 6 patients (response rate 32%), 3 of them occurring in 10 patients with primary platinum resistance. Conclusions: HDE is tolerable and has activit y in second-line after cisplatin-based chemotherapy in OC patients. The rec ommended dose for phase II trials in such patients is 150 mg/m(2), with esc alation to 180 mg/m(2) if toxicity permits.