Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer

Background: Anthracyclines and taxanes are the most active drugs against br east cancer and the search after their optimal combination is under intensi ve investigation in both the advanced and early disease settings. A dose-fi nding study of epidoxorubicin (E) and docetaxel (D) was conducted in advanc ed breast cancer (ABC) to define the maximum tolerated dose (MTD) of the co mbination with and without granulocyte colony-stimulating factor (G-CSF) su pport and to characterise its toxicity and activity profile. Patients and methods: Forty-two patients who received neither palliative ch emotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with greater than or equal to 2 sites involved) with measurable/eva luable lesions, were treated at four dose levels starting from E 75 mg/m(2) and D 75 mg/m(2) to E 120 mg/m(2) and D 85 mg/m(2). A maximum of four cycl es of the combination was given every three weeks and four additional cycle s of single agent D were allowed in responding patients. Cardiac function w as monitored at baseline and at every second course by echocardiography. Results: Febrile neutropenia (two patients) and prolonged, severe neutropen ia (absolute neutrophil count (ANC) < 0.1 x 109/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m(2) and D 75 mg/m(2). G-CSF was then routinely administered from th e subsequent dose level of E 120 mg/m(2) and D 75 mg/m(2). The MTD with G-C SF support was established at E 120 mg/m(2) and D 85 mg/m(2) (one patient w ith neutropenic fever together with failure of ANC recovery at day 21, thre e patients with ANC less than 0.1 x 10(9)/l for more than three days, one p atient with both and one patient with grade 4 thrombocytopenia and toxic de ath from typhlitis while neutropenic). No severe neurotoxicity, mucositis, or fluid retention were observed and there were no clinical signs of cardio toxicity. Antitumour activity was not a primary endpoint of the study: the overall response rate (ORR) in 40 evaluable patients was 60% (95% confidenc e interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no appa rent dose-related effect. After a median follow-up of 19 months (range 2-30 +), the overall time to progression (TTP) in nine patients without maintena nce hormonal therapy was five months. Conclusions: The combination of E and D proved to be an effective and safe regimen in poor- prognosis patients with ABC. G-CSF support allowed higher doses to be delivered safely but dose escalation did not translate into imp roved response rates (RR). The MTD without growth factors support was used, in a phase II trial, which also included patients with previous anthracycl ine-containing adjuvant regimens.