A multicenter phase I-II trial was carried out with the aim of identifying the dose-limiting toxicity and the maximum tolerated dose of vinorelbine (VNR) in combination with pegylated liposomal doxorubicin at a dose of 20 mg/m² every 15 days in patients with metastatic breast carcinoma. In the phase I part of the trial, VNR was given at a dose of 20 mg/m² every 15 days to a group of 3 patients. In absence of unacceptable toxicity, VNR was escalated to 25, 30, and 35 mg/m² for subsequent groups of 3 patients, until the dose-limiting toxicity was reached. No case of palmar-plantar erythrodysesthesia was recorded in these patients. Grade 4 neutropenia, grade 3 thrombocytopenia, and grade 3 mucositis were the dose-limiting toxicities recorded in patients treated with VNR 35 mg/m². These side effects caused a substantial decrease in programmed dose intensity. Therefore 30 mg/m² was considered the maximum tolerated dose of VNR in combination with pegylated liposomal doxorubicin 20 mg/m², both given every 15 days. These dosages were employed for the treatment of further 18 patients included in phase II of the study. The overall response rate, calculated according to an intention to treat analysis, was 63% (95% CI: 44–80%), with 2 patients achieving a complete response. The median time to progression was 7.0 months or more (range 2–14 months). Median duration of objective responses was 8.4 months or more. The duration of the 2 complete responses was 9 and 14 months, respectively. Median duration of survival was 16.0 months or more (range from 4.0 to ≧24.0). Toxicity was generally mild and easily manageable. Neutropenia and mucositis were the most frequently recorded side effects. A case of palmar-plantar erythrodysesthesia was recorded in phase II of the study. In conclusion, the maximum tolerated dose of VNR in association with pegylated liposomal doxorubicin is 30 mg/m² on a bimonthly schedule. Moreover, the combination of VNR and pegylated liposomal doxorubicin is active against metastatic breast carcinoma and is associated with a good toxicity profile. Further studies with this combination regimen are warranted.

Our objective was to identify a new active three-drug combination regimen consisting of paclitaxel (PTX), epirubicin (EPI) and cisplatin as first-line line chemotherapy for advanced ovarian carcinoma. A phase I study was carried out to evaluate the dose-limiting toxicity (DLT) and the maximally tolerated dose (MTD) of PXT and EPI in combination with a fixed dose of cisplatin every 4 weeks. Side-effects were recorded according to the NCI Common Toxicity Criteria. Patients were treated in cohorts of three with fixed-dose cisplatin 80 mg/m2 and EPI 80-->100 mg/m2 and PXT 100-->160 mg/m2 until DLT was reached. Once MTD was identified, a single-step phase II study was therefore carried out to test the clinical activity and panel of toxicity of such regimen. Objective responses were recorded according to the WHO criteria. Time to progression and overall survival (OS) were secondary endpoints. The DLT was myelosuppression and, in more detail, febrile neutropenia, which occurred at the fifth dose level (PTX 140 mg/m2, EPI 100 mg/m2 and cisplatin 80 mg/m2) in two out of three patients. Other side-effects were grade 3 mucositis in two out of three patients and grade 3 anemia in one case. The combination of cisplatin 80 mg/m2 plus EPI 80 mg/m2 and PCT 140 mg/m2 every 4 weeks was considered as the MTD. In the phase II study a complete response was observed in six patients (33%) and a partial response in nine cases (50%) for an overall response rate of 83% [95% confidence limits (CL) 59-96%]. Median time to progression of patients with measurable disease was 16.4 months. Median OS was not reached after a follow-up of 42 months. This study demonstrated that PTX and EPI can be safely administered in combination with cisplatin to fit patients with advanced epithelial ovarian carcinoma. The three-drug regimen of cisplatin 80 mg/m2, EPI 80 mg/m2 and PTX 140 mg/m2 every 4 weeks is very active, at least in terms of objective response rate. This level of activity overlaps with the 95% CL of the activity of cisplatin alone; however, it does encourage future trials of the combination.

e11527 Background: Several studies demonstrated the efficacy of neoadjuvant trastuzumab in breast cancer patients. However, cardiotoxicity intrinsic and increased by combining anthracyclines or chest wall radiotherapy remains a ticklish issue, mainly when is durable and occurs in potentially healable young patients. Methods: A phase II study of neoadjuvant trastuzumab and sequential chemotherapy was started in the late 2007 at Humanitas CCO and enrolled 42 patients with stage II-III HER2-positive breast cancer. Treatment consisted of 18 administrations of weekly trastuzumab combined with a sequential regimen including 3 courses of cisplatin 80 mg/m2 d1 + vinorelbine 25 mg/m2 d1 and d8 q3w followed by 3 courses of docetaxel 100 mg/m2d1 q3w. Peg-filgrastim was given in each course. Postoperative trastuzumab q3w was administered for one year. Radiant and endocrine therapy were delivered according to standard practice. Primary objective was the rate of pathologic complete response (pCR), now defined as no evidence of residual invasive cancer, both in breast and lymph nodes. A first report of the study was presented as poster at ASCO 2010. Results: With regard to real patient characteristics observed in the daily clinical practice, no restrictive sample selection was established and the eligible patients were accrued consecutively. Median age was 48 (range 23-71). Twenty-three patients (55%) had stage III tumors and 7 of them stage IIIB, including 4 cases of tumor spreading to skin (T4b) and 3 cases of inflammatory carcinoma (T4d). Seventeen patients (40%) had tumor with no expression of hormone receptors and 36 (86%) with ki67≥14%. The rate of pCR was 26% (11/42). Among 29 women initially candidate to radical mastectomy, 13 of them (45%) finally received breast-conserving surgery and 8 skin-sparing mastectomy. Treatment was well tolerated and produced only moderate alopecia and no case of significant LVEF decrease. Conclusions: Neoadjuvant trastuzumab combined with the above non-anthracycline-containing sequential chemotherapy may be considered a safe and effective regimen in HER2-positive breast cancer patients. Clinical trial information: 2006 000392 15.

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e11559 Background: Recently, some studies have demonstrated benefit from adding trastuzumab to neoadjuvant anthracycline-containing chemotherapy for HER2-positive breast cancer patients. However, trastuzumab can increase cardiotoxicity, particularly when combined with anthracyclines. This represents a relevant issue for patients who usually need to receive radiotherapy or further systemic treatment. Methods: In the late 2007 we started a phase II study for testing activity and safety of neoadjuvant trastuzumab in association with sequential chemotherapy, based on favourable in vitro combination index, proven efficacy, and moderate cardiotoxicity. Weekly trastuzumab for 18 weeks was combined with cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1+8 q3w for 3 courses, followed by docetaxel 100 mg/m2 q3w for further 3 courses. Peg- filgrastim was administered to prevent neutropenia. Adjuvant trastuzumab q3w was planned for one year. Eligible patients had stage II-III core-biopsied breast carcinoma with overexpressed or amplified HER2/neu. Adequate cardiac function with LVEF ≥ 50% was required for trastuzumab administration. Primary end-point was pathologic complete responses (pCR) rate. The study is registered on the European Clinical Trials Database. Results: Among 17 enrolled patients, 15 were evaluable for primary end-point. Median age was 50 years (range 23–70), stage II and III breast cancer in 4 and 13 patients, respectively, with 4 cases of stage IIIB (2 T4b and 2 T4d), and 2 women with synchronous bilateral cancer. Neoadjuvant regimen yielded 6/15 pCR (40%). Only 3/12 patients treated with lymphadenectomy due to initial clinically suspected axillary nodes presented pN+, but none of them had more than 3 positive nodes. In two cases we observed a total pCR, involving both primary tumor and axillary nodes. Treatment was safe, with only 2 events of short G4 non febrile neutropenia on 97 chemotherapy cycles. Alopecia was moderate at the end of treatment, without any case of complete hair loss. No significant cardiac dysfunction was recorded during the neoadjuvant therapy. Conclusions: The present sequential non anthracycline-based chemotherapy associated with weekly trastuzumab showed promising results in neoadjuvant setting. No significant financial relationships to disclose.