Dose Escalation Study of Epirubicin and Docetaxel in Patients with Advanced or Recurrent Breast Cancer

Background: Anthracyclines and taxanes are major cytotoxic drugs against breast cancer. To develop a combination of epirubicin (EPI) and docetaxel (DTX) in Japan, dose escalation and pharmacokinetic studies were performed in patients with advanced or recurrent breast cancer. Methods: Twenty patients received EPI (40, 50 or 60 mg/m2) as 5-min intravenous infusion, followed by DTX infusion (50 or 60 mg/m2) over 1 h in cohorts of 3–6 patients. The maximum tolerated dose (MTD) was defined during the first cycle when more than 2 of 3 or 3 of 6 patients suffered a dose-limiting toxicity (DLT). The DLT was based on febrile neutropenia (FN), prolonged neutropenia, thrombocytopenia and grade 3–4 nonhematological toxicity during the first cycle. Plasma sampling was performed to assess the pharmacokinetic study of these drugs. Results: The second level (EPI/DTX 50/50 mg/m2) was found to be a maximum tolerated dose because of a short duration of FN with no distress. Subsequently, the protocol was modified to permit a new DLT definition including FN lasting for more than 72 h. At the following levels of EPI/DTX 50/50, 50/60 or 60/60 mg/m2, the dose escalation study revealed a high incidence of grade 4 neutropenia (100%) and FN (67%), which did not reach DLT. However, the safety committee decided not to go further because of too high an incidence of FN lasting 3 days, although a little less than 72 h. The pharmacokinetic study with a combination of EPI and DTX showed comparable blood levels of DTX and EPI in relation to those seen when given alone. Conclusion: For further evaluation, the recommended dose and schedule of this combination is EPI 60 mg/m2 and DTX 60 mg/m2, given every 3 weeks to patients without prior chemotherapy and EPI 50 mg/m2 and DTX 50 mg/m2 given to patients with prior chemotherapy, respectively. The pharmacokinetic study indicates no interaction between EPI and DTX.