Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group

Purpose: To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. Patients and Methods: Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m(2) of epirubicin intravenously (IV) every 3 weeks, Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m(2), dose escalation to 135 mg/m(2) was performed. A full pharmacokinetic analysis was performed in 78 patients. Results: Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m(2), while no increase in efficacy was found from 90 to 135 mg/m(2), Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m(2) was an independent prognostic covariate. Furthermore, a significant association was established between randomised dose and both hematologic and nonhematologic toxicity, No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. Conclusion: An increase in dose of epirubicin from 40 to 90 mg/m(2) is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established. (C) 1996 by American Society of Clinical Oncology.