Front-line treatment of metastatic breast cancer with docetaxel and epirubicin: A multicenter dose-escalation study

Purpose: To determine the maximum tolerable dose (MTD) and the dose-limitin g toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in p atients with advanced breast cancer. Patients and methods: Forty-seven chemotherapy-naive metastatic breast canc er patients aged < 75 years with PS (WHO) 0-2 and adequate bone marrow, ren al, liver and cardiac function, were enrolled in the study. Epi was given a s a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with incr ements of 10 mg/m(2); D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increment s of 10 mg/m(2). The patients' median age was 60 years, 42 (89%) had a PS ( WHO) 0-1, 16 (34%) were premenopausal and 25 (53%) had visceral disease. Results: When the two drugs were given on the same day, the MTD1 was reache d at the doses of Epi 60 mg/m(2) and D 80 mg/m(2); administration of G-CSF could not result in a dose intensification. When the drugs were given on tw o consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m(2) (d( 1)) and D 90 mg/m(2) (d(2)). The dose-limiting events were febrile neutrope nia and grade 4 neutropenia, which developed in 30 (64%) patients during th e study; among 227 delivered cycles grade 3-4 neutropenia occurred in 64 (2 8%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine (19%) pa tients, mild edema in eight (17%) and allergic reactions in five (11%). Fou r (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients develope d congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is consi dered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The med ian survival has not yet been reached. Conclusions: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.