Gemcitabine, ifosfamide, cisplatin (GIP) for the treatment of advanced non-small cell lung cancer: a phase II study of the italian oncology group for clinical research (GOIRC).

The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosfamide and cisplatin (GIP) in chemonaive patients with advanced non small cell lung cancer (NSCLC). Eighty chemonaive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m(2) on Days 1 and 8, ifosfamide 2 g/m(2) on Day 1 and cisplatin 80 mg/m(2) on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were transfused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0-114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial.

Plain and drug loaded polyphosphazene membranes and microspheres in the treatment of rabbit bone defects.

The healing of periodontal surgical defects was studied in rabbits, using polyphosphazenes (POP) membranes and microspheres, both plain or drug-enriched. POP polymers having amino acid ester as backbone substituents, are used since they resorb and undergo hydrolytic degradation to ammonia, phosphate and amino acids. Fourteen animal were operated in tibia, and other fourteen at angle of the mandible, that was reached by extraoral access. Bone defects were performed in tibiae, and covered either with POP or with poly-tetrafluoroethylene (PTFE) membranes, while other rabbits served as controls. The animals were sacrificed after one and two months, and the tibiae taken and processed for optical microscopy. Similar surgical defects were made in mandible, and POP membranes were placed over the breaches, some of which were filled with POP microspheres, both alone or mixed with granular hydroxyapatite. For comparison, two rabbits were treated with PTFE membranes, while other two served as controls. The animals operated at the mandible were all sacrificed after one month, and the operated bones taken and processed for histology. It was found that POP membranes were very effective in promoting the healing in tibiae, while less satisfactory results were found in the animals treated with PTFE membranes and in controls. In mandible, the healing occurred without a clear relationship with the grafted microgranular material or the membrane, since repairing bone was found also in controls. In any case, both POP membranes and microspheres showed excellent biocompatibility, as no inflammatory cells or macrophages were found in the surrounding tissue. This property was completely independent from the presence of drug, since the matrix-entrapped drugs, released in the tissue, did not hamper the bone healing. It was also found that POP, by itself, has a positive effect in stimulating the bone repair.

Three new active cisplatin-containing combinations in the neoadjuvant treatment of locally advanced and locally recurrent breast carcinoma: a randomized phase II trial.

We designed three new four-drug cisplatin-containing combinations and evaluated their activity in a randomized phase II study including patients with locally advanced (stage III) and locally recurrent breast carcinoma. All combinations included methotrexate (M) on day 1 and cisplatin (P) on day 2 (MVAC-like combinations) and differed from one another by the addition of Epirubicin (Epi), Vincristine (V), Etoposide (E), Mitomycin (Mi). Based on the administered agents, they were named MPEMi, MPEpiE, MPEpiV. The combinations were randomly assigned to 101 patients, 57 with locally advanced and 44 with locally recurrent breast carcinoma. Response was evaluated after 4 cycles. The complete response (CR) rates were 7% and 43% and the CR plus partial response (PR) rates were 84% and 89% in locally advanced and in locally recurrent disease, respectively. In locally advanced disease, a pathologic CR (pCR) was assessed in seven of 57 patients (12%). There were no significant differences among the three combinations. The toxicities were at times severe, but generally tolerable, as demonstrated by the high cumulative doses of the drugs received by the patients. In conclusion, these three innovative chemotherapy regimens induced high CR plus PR rates in the neoadjuvant treatment of stage III and of locally recurrent breast carcinoma, and a high rate of pCR in stage III disease. These regimens warrant testing in phase III trials.

Ifosfamide bolus followed by five days continuous infusion in extensively pretreated patients with advanced breast cancer: a phase II study.

PURPOSE: A phase II study with ifosfamide in pretreated patients with advanced breast cancer was performed to determine the objective response rate, the toxicity and the feasibility of the regimen. METHODS & STUDY DESIGN: Patients enrolled had advanced breast cancer pretreated with at least one previous regimen of chemotherapy for advanced disease. Treatment consisted of ifosfamide infused at a dose of 2 g/m2 iv in 4 hrs followed by ifosfamide, 8 g/m2 iv in 120 hrs in ambulatory treatment, using a portable external pump system. The total dose of ifosfamide was 10 g/m2; mesna (4 g/m2 iv) was administered mixed with ifosfamide in 120 hrs Cycles were repeated every 3 weeks. Three patients were pretreated with neoadjuvant and 15 with adjuvant chemotherapy. All patients were treated for advanced disease (median number of regimens, 1; range, 1-3): 21 with the cyclophosphamide-containing regimen and 15 with adryamicin. Sixteen patients received one or more lines of endocrine therapy. Fifteen patients had dominant site in viscera, 6 in bone, and only one in soft tissue; 17 patients had more than one site of disease. RESULTS: Twenty-two patients were enrolled and all were assessable for response and toxicity. A partial response was reached in 5 patients (23%; 95% confidence limits 5% to 60%). Hematologic toxicity was the dose-limiting side effect; grade 4 leukopenia occurred in 10 patients (46%). CONCLUSIONS: Considering the response rate obtained in our series of intensively pretreated patients, the results seem to indicate that the regimen is active and could be included among the possible options in the treatment of patients with refractory, poor-prognosis, advanced breast carcinoma.

Bolus versus 5-day continuous infusion of cisplatin with mitomycin and vindesine in the treatment of advanced non-small cell lung cancer (NSCLC): a phase III prospective randomised trial of the Italian Oncology Group for Clinical Research (GOIRC).

The aim of this randomised trial was to compare the efficacy of bolus versus continuous infusion cisplatin combined with mitomycin C and vindesine (MVP) for chemotherapy-naive patients with stage IIIB-IV non-small cell lung cancer (NSCLC). 97 patients (49 given bolus cisplatin-arm A and 48 given continuous infusion cisplatin--arm B) were evaluable for response. In arm A, 2 patients achieved a complete response (CR), 21 achieved a partial response (PR), whilst in arm B, 14 patients achieved a PR (29%) (P = 0.07). Median survival was 8 months in both arms. Myelosuppression was the most frequent and severe toxicity, with a higher incidence of grade 3-4 leucopenia in arm A when compared with arm B (44% versus 25%). In conclusion, there is no advantage for a cisplatin 5 day infusion in the MVP regimen.

Neoadjuvant chemotherapy with continuous infusion of cisplatin and fluorouracil in stage II-IV, M0 squamous cell carcinoma of the head and neck.

AIMS AND BACKGROUND: The aim of the study was to assess the activity and the toxicity of cisplatin (DDP) and fluorouracil (FU) administered by continuous infusion as neoadjuvant chemotherapy for patients with stage II-IV, M0 squamous cell carcinoma of the head and neck. METHODS: Thirty previously untreated patients were submitted to chemotherapy with DDP (20 mg/m2) and FU (1000 mg/m2), both in continuous infusion for 5 days, repeated every 21 days, for a maximum of 5 cycles. Following completion of chemotherapy, the patients underwent radiotherapy; in some patients surgery was performed immediately after chemotherapy. All patients were monitored for response, time to failure, survival, treatment-related events and toxicity. RESULTS: All patients were evaluated for response; after chemotherapy the complete response rate was 27% and the partial response rate 33%. Twenty-four patients underwent radiotherapy: the overall response rate was 83% (complete response 79%). After a median follow-up of 34 months, the median survival time was 22 months with a median time to failure of 15 months. Acute vascular accidents were the main and unexpected adverse events, with 2 deaths for pulmonary embolism and 1 for stroke. The response rate to the regimen does not seem to be better than that obtained with the standard combination of cisplatin bolus and fluorouracil continuous infusion. The disadvantage of the regimen is that it causes more discomfort for the patient in that it requires hospitalization. CONCLUSIONS: For this reason, we believe that there are no elements for recommending the schedule as neoadjuvant treatment of patients with squamous cell carcinoma of the head and neck or as an experimental arm in a randomized trial.