Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients

Purpose: To determine the maximum tolerated dose (MTD) and the dose limitin g toxicity (DLT) of docetaxel in combination with fixed doses of epirubicin . Patients and methods: Women with locally advanced or metastatic breast canc er were given docetaxel, 60 mg/m(2) in escalated doses by steps of 10 mg/m( 2), in association with two fixed doses of epirubicin (90 mg/m(2), and 75 m g/m(2)). Since neutropenia was foreseen to be the most likely DLT, a third group with prophylactic G-CSF support was planned to define the MTD of doce taxel with 90 mg/m(2) of epirubicin. Selected patients underwent pharmacoki netic evaluation of docetaxel. Results: Fifty-eight patients entered the study. At the first step (90 mg/m (2) of epirubicin) the MTD was obtained at 60 mg/m(2) of docetaxel. At the second step (75 mg/m(2) of epirubicin) the MTD of docetaxel was 80 mg/m(2). At the third step (epirubicin 90 mg/m(2)) G-CSF allowed a safe escalation of docetaxel up to 90 mg/m(2). Neutropenia was the most common hematologica l adverse event. Without G-CSF, grade 4 neutropenia occurred in 69% of cycl es, of which 11% was complicated by fever. In G-CSF group, grade 4 neutrope nia and neutropenic fever occurred in 31% and 3%, respectively. Most freque nt non-hematological adverse effects were asthenia (45%), nausea (39%) and mucositis (36%). No patient developed congestive heart failure. Two toxic d eaths occurred. Overall response rate was 73% in 42 out of 58 patients, wit h no apparent epirubicin dose-related effect. No statistically significant effect of the two doses of epirubicin was observed in docetaxel pharmacokin etics. Conclusions: On the basis of the toxicity profile, the docetaxel pharmacoki netics and the response rate observed, epirubicin 75 mg/m(2) combined with docetaxel 80 mg/m(2) can be recommended for further studies.