"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

BACKGROUND: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). METHODS: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. RESULTS: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). CONCLUSIONS: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses.

Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site.

The aim of this study was to assess the activity and toxicity of a platinum-based treatment on a group of patients with unknown primary tumours (UPTs). Patients with a diagnosis of UPT underwent a standard diagnostic procedure. Treatment was started within 2 weeks from diagnosis and consisted of carboplatin 400 mg m(-2) day 1, doxorubicin 50 mg m(-2) day 1, etoposide 100 mg m(-2) days 1-3, every 21 days. Response was evaluated after three courses and treatment continued in case of objective response (OR) or symptom control. A total of 102 patients were eligible. The median age was 59 years, sex male/female 54/48, histology was mainly adenocarcinoma or poorly differentiated carcinoma. Nodes, bone, liver and lung were the most frequently involved sites. In all, 79 patients received at least three courses of treatment; 26 patients received six courses or more. Six complete responses and 21 partial responses were observed, for a total of 27 of 102 ORs or 26.5% (95% confidence interval 18.2-36.1%). The median survival was 9 months and median progression-free survival was 4 months. Toxicity was moderate to severe, with 57.8% of patients experiencing grade III-IV haematological toxicity, mainly leucopenia. The regimen employed has shown activity in tumours of unknown primary site, but was associated with significant toxicity. Such toxicity may be considered unjustified, given the large proportion of patients with tumours not likely to respond. Efforts should therefore be addressed to identify predictors of response to chemotherapy, thus limiting aggressive treatment to those patients who could benefit from it.

A new cisplatin/gemcitabine schedule in locally advanced (IIIB) and metastatic (IV) non-small cell lung cancer: relationship between dose-intensity and efficacy. A phase II study.

BACKGROUND: Cisplatin/gemcitabine are one of the "standard" chemotherapy schedules in locally advanced and metastatic NSCLC cancer. A number of trials documented that omission of gemcitabine on day 15 and reduction of cisplatin up to 70 mg/mq are equivalent in term of response rates to "classic" administrations on days 1, 8 and 15 with cisplatin 100 mg/mq. The aim of this study was to confirm this evidence and to demonstrate that a further reduction of gemcitabine dose-intensity may be performed with the same efficacy on response. PATIENTS AND METHODS: Fifty untreated patients with locally advanced and metastatic NSCLC entered the study: 24 stage IIIB and 26 stage IV. The median age was 65 years (range 32-76); 44 males and 6 females Genicitabine was administered 1000 mg/mq weekly on days 1 and 8 followed by a 2-week rest and cisplatin 80 mg/mq on day 2 of each 28-day-cycle. RESULTS: Forty-five patients were evaluable for response and all for toxicity. The overall response rates were 35.5% with 16 partial responses (95% Confidence Interval: 32%-61%). Most of the objective responses were seen in IIIB patients (56% of the stage IIIB and 44% of the stage IV patients responded). According to the intent-to-treat-principle, the response rates were 32% (16 out of 50 patients). The median dose-intensity of gemcitabine and cisplatin was respectively 477.6 mg/mq/week (481.4 for responders) and 19.5 mg/mq/week (19.9 mg/mq for responders). The median response duration was 5 months (range 1-18) and the median time to progression was 5 months (1-21); median survival was 9 months (range 2-31). The main toxicity was haematological: thrombocytopenia grade IV in 5 patients (10%) and grade III in 11 patients (22%); neutropenia grade III-IV in 4 patients (8%); grade III anemia in 3 (6%). Asthenia was the most significant non-haematological toxicity and was observed in 19 patients (38%). CONCLUSION: This trial confirmed the efficacy of a schedule with 2 administrations of gemcitabine (on days 1, 8) and a cisplatin dose on day 2 lower than 100 mg/mq. Moreover, the same efficacy was obtained with a median-dose intensity of cisplatin and gemcitabine lower than planned in a 21-day-schedule. For safety and low toxicity, we think that this schedule provides another chance to treat patients with non-small cell lung cancer, especially the elderly or patients with coexistent medical illnesses.