DOSE-RESPONSE RELATIONSHIP OF EPIRUBICIN IN THE TREATMENT OF POSTMENOPAUSAL PATIENTS WITH METASTATIC BREAST-CANCER - A RANDOMIZED STUDY OF EPIRUBICIN AT 4 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 metasta tic breast cancer. The study also included analysis of a correlation b etween pharmacokinetic and pharmacodynamic parameters. Patients and Me thods: Two hundred eighty-seven women were randomized to receive eithe r 40, 60, 90, or 135 mg/m(2) of epirubicin intravenously (IV) every 3 weeks, Treatment consisted of first-line cytotoxic therapy for metasta tic disease. In patients with early progressive disease after either 4 0 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 progre ssion 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 progr ession as the end point, confirmed that epirubicin dose more than 60 m g/m(2) was an independent prognostic covariate. Furthermore, a signifi cant association was established between randomised dose and both hema tologic and nonhematologic toxicity, No association between pharmacoki netic parameters and efficacy parameters was demonstrated. On the othe r hand, a significant correlation between pharmacokinetic parameters a nd both hematologic and nonhematologic toxicity was found. Conclusion: An increase in dose of epirubicin from 40 to 90 mg/m(2) is accompanie d by increased efficacy. Further increases in dose do not yield increa sed efficacy. A positive correlation between epirubicin dose and toxic ity, as well as a correlation between pharmacokinetic parameters and t oxicity, was also established. (C) 1996 by American Society of Clinica l Oncology.