Vici et al. Journal of Experimental & Clinical Cancer Research 2011, 30:39 http://www.jeccr.com/content/30/1/39 Page 3 of 8 (G-CSF) subcutaneously on days 7-12 of each cycle, or (arm B) PLD 40 mg/m2 i.v. on day 1, plus VNB 30 mg/ m2 on days 1 and 15. Cycles were repeated every 21 days in arm A, and every 28 days in arm B, for a maximum of 8 cycles. Treatment was continued until disease progression, severe toxicity, patient refusal. Antiemetic treatment consisted of an antiserotonin agent plus desamethasone in a 15 min infusion before starting chemotherapy. Treatment was postponed by a maximum of 2 weeks if the absolute neutrophil count was less than 1,500/μL or the platelet count was less than 100,000/μL. A 25% drugs dose-reduction was planned in case of grade 4 neutropenic fever, as well as in case of grade 3 mucositis or neurotoxicity. G-CSF was administered in arm B in case of grade 4 neutrope- nic fever, and prophylactively in the subsequent cycles. Treatment was discontinued in case of grade 4 neuro- toxicity, mucositis, palmar plantar erythrodisesthesia (PPE), treatment delay longer than 2 weeks, or in case of cardiotoxicity, defined as LVEF decrease ≥ 20% from baseline, or ≥10% but with a value below 50%, or any symptoms of congestive heart failure or arrhythmias even in absence of LVEF decrease. Hematologic assess- ment was done on days 1 and 12 of every cycle in arm A, and on days 1 and 14 in arm B, and whenever useful at discretion of investigator. Pretreatment and Follow Up Studies Pretreatment investigations included complete blood count and chemistry, chest x-ray, bone scan, CT abdo- men, LVEF evaluation by echocardiography, and other site-specific imaging as appropriate. Echocardiography with LVEF evaluation had to be performed every 3 cycles, or whenever indicated at discretion of investiga- tor; during the follow-up LVEF had to be determined every 6 months. Evaluation of Response and Toxicity Tumor assessment was performed every 3 cycles, or whenever appropriate, and responses were evaluated according to RECIST criteria [31]. Progression free sur- vival (PFS) was calculated starting from the date of ran- domization to the date of disease progression, refusal or death from any cause; overall survival (OS) was calcu- lated starting from the date of randomization to the date of death or last follow up evaluation. Toxicity was assessed in each cycle according to National Cancer Institute Common Toxicity Criteria (version 3.0). Statistical Methods The primary objective of the study was to evaluate the overall response rate of the two regimens, secondarily toxicity, progression free survival and overall survival. The study was designed as a phase II trial with a ran- dom assignement to a calibration arm A and to an experimental arm B. The sample size for arm B was cal- culated according to the design described by A’Hern [32]. A sample size of 53 patients was considered suffi- cient to give a 90% probability of rejecting a baseline response rate of 35% with an exact 5% one-sided signifi- cance test when the true response rate was 55%. The drug regimen should have been considered for further studies if at least 25 responses were observed. The cali- bration arm had the same sample size. No formal com- parison was planned. The objective response rate have been reported with its 95% confidence interval. All patients enrolled were considered in the intention-to- treat population (ITT). This population have been eval- uated for the efficacy analysis, which was performed also on evaluable patients. Subjects who assumed at least one dose of drug have been considered as denomi- nator in the safety analysis. The time to event analysis was performed according the Kaplan-Meier method. Results Patients Characteristics From March 2003 to November 2005, a total of 104 patients were enrolled from 4 oncologic centers of the GOIM (Gruppo Oncologico Italia Meridionale), with 54 patients randomized to arm A (EPI/VNB) and 50 patients to arm B (PLD/VNB). All randomized patients have been evaluated for activity and toxicity according to ITT analysis. Patient characteristics are listed in Table 1. None of the patients have received any chemotherapy for advanced disease; 20 patients in arm A and 21 patients in arm B had received adjuvant chemotherapy, not including anthracyclines or vinka alcaloids; 35 and 30 patients had received previous adjuvant hormonal therapy, and 10 and 11 patients had received endocrine treatment for advanced disease in arm A and B, respectively. Median age was 63 and 61 years, 10 and 9 patients were premenopausal, 44 and 41 postmenopausal in arm A and B, respectively; dominant site of disease was soft tissue in 3 (5.6%) and 9 (18.0%), bone in 11 (20.4%) and 9 (18.0%), viscera in 40 (74.0%) and 32 (64.0%) patients in arm A and B, respectively. Hormonal receptors were positive (ER and/or PgR) in 39 and 32 patients, negative in 13 and 15 patients, unknown in 2 and 3 patients in the two arms, respectively. Her-2, retrospectively evaluated in 35 and 38 patients in arm A and B, was overexpressed or amplified in 8 patients in each arm (14.8% and 16%, respectively). The median number of chemotherapy cycles administered was 6 in both arms (range, 1 to 8 in both arms).