Vici et al. Journal of Experimental & Clinical Cancer Research 2011, 30:39 http://www.jeccr.com/content/30/1/39 Page 2 of 8 Background Anthracyclines are among the most active drugs in advanced breast cancer, with response rates as single agents of approximately 30% to 50%, and anthracycline- based regimens have been shown to determine significant advantages in response rate and progression free survival over non- anthracycline-containing regimens [1,2]. The potential benefit of conventional anthracyclines, mainly doxorubicin, is limited by the risk of cardiac dysfunction, clearly related to cumulative dose, and as a result it might be necessary to withdraw treatment or to avoid re-treatment even in potential responders patients. To minimize toxic effects, doxorubicin has often been replaced by epirubicin (EPI), known to be as active as the parent compound and with lower toxicity, particu- larly cardiac toxicity [3-6]. As dose-response concerns, higher EPI doses, both as single agent and in combina- tion regimens, seem to be more efficacious than lower doses [7-10]. Vinorelbine (VNB) has established activity as single- agent in breast cancer, both as first-line and salvage treat- ment [11,12], and its good tolerance profile makes it an excellent candidate for combination regimens, so it was a logical step to combine VNB with anthracyclines, and the combination with doxorubicin yielded a 74% of response rate, a median duration of response of 12 months and a median survival of 27.5 months as first-line treatment [13]. Other trials employing this combinations confirmed positive results [14-16]. Preliminary results of a rando- mized phase III trial comparing VNB 25 mg/m2 on days 1,8 in combination with EPI 90 mg/m2, with EPI as single agent, showed a trend for higher response rate (50% vs 42%) and a significantly longer progression free survival (10.1 vs 8.2 months) for the combination arm [17]. An our previous clinical study with EPI/VNB combination as first-line treatment showed a very high activity (70.6% of response rate) and acceptable toxicity [18]; another our experience testing the sequential administration of doce- taxel for 4 cycles followed by 4 cycles of EPI/VNB as first-line treatment for advanced disease, confirmed activ- ity and tolerability of the regimen [19]. Incapsulating drugs in liposomes determine improve- ment of solubility and stability of the drug, and prevent a rapid degradation; moreover, specific toxicities are poten- tially lowered and the efficacy increased, achieving a higher therapeutic index [20]. Liposomal anthracyclines exhibit efficacies comparable with those of conventional anthracyclines, but with better safety profiles [21-24]. In particular, data from retrospective analyses showed that liposomal anthracyclines significant reduced the risk of cardiotoxicity compared with conventional anthracy- clines [25]. Phase III trials comparing pegylated liposomal doxorubicin (PLD) with conventional anthracyclines confirmed similar efficacy and lower toxicity than doxor- ubicin [24,26], and results of several studies have shown that PLD is effective in combination with other drugs including taxanes, cyclophosphamide, gemcitabine [27]. As cardiotoxicity concerns, in a retrospective analysis a low incidence of cardiac side effects were reported, even at cumulative doses higher than 500 mg/m2 [28]. The combination of PLD with VNB was investigated in anthracycline pretreated patients, with promising results and manageable toxicity [29,30], but at the time we design the present study no information about its first- line use in comparison with a conventional anthracy- cline-containing regimen were available, so we carried out a prospective multicenter phase II randomized trial of EPI/VNB versus PLD/VNB as first-line treatment for advanced disease in patients not previously treated with adjuvant anthracyclines. Patients and Methods Patient selection Patients with histologically proven advanced breast cancer not previously treated with adjuvant anthracyclines were enrolled. Eligibility criteria included a life expectancy > 3 months, 18 to 75 years of age, WHO performance status ≤ 3, measurable/assessable disease, adequate bone marrow (absolute neutrophil count ≥1,500, platelet count ≥ 100,000, haemoglobin ≥ 11 g/dL), renal and liver function (total bilirubin and creatinine <1.25 times the upper nor- mal limits), and a normal cardiac function (left ventricular ejection fraction LVEF ≥ 50% by echocardiography). Patients were excluded from the study if they had active cardiac diseases or significant arrhythmias, pre-existent neuropathy, or had received prior chemotherapy treatment for advanced disease, prior exposure to anthracyclines and or vinorelbine, or if they had prior or concomitant malig- nant disease, except appropriately treated basal cell carci- noma of the skin or in situ carcinoma of the cervix. Previous adjuvant chemotherapy with cyclophosphamide, methotrexate, fluorouracil or similar regimens were allowed, but an interval of two months should have elapsed; hormonal adjuvant treatment and radiotherapy must have been discontinued for at least 4 weeks before study entry. The protocol was approved by the ethical committees of each participant centers, and was carried out according to Helsinki declaration and in accordance with the International Conference on Harmonization Good Clinical Practice guidelines. Treatment Patients were centrally assigned according to a compu- ter generated random list to receive either (arm A) EPI 90 mg/m2 i.v. on day 1 plus VNB 25 mg/m2 i.v on days 1 and 5, with granulocyte colony-stimulating factor