Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810).

PURPOSE: The purpose of this open-label phase II SWOG study was to evaluate the activity of gemcitabine (Gemzar; Eli Lilly, Indiana, USA) and cisplatin combination therapy, in patients with unresectable malignant mesothelioma of the pleura. PATIENTS AND METHODS: Fifty eligible chemotherapy naïve patients with histologically proven malignant mesothelioma of the pleura, and a SWOG performance status 0-2 were enrolled between February 1999 and August 2000. Treatment consisted of gemcitabine 1000mg/m(2) and cisplatin 30mg/m(2) on days 1, 8 and 15 of a 28-day cycle, until progression of disease or two cycles beyond complete response. RESULTS: Using SWOG response criteria, one patient had a confirmed complete response and five patients had a confirmed partial response, for a total response rate of 12% (95% CI 5-24%). All the responses were seen in patients with epithelioid or unspecified histology. Stable disease was seen in 25 patients (50%). The median overall survival was 10 months (95% CI 7-15 months), with a median progression-free survival of 6 months. Sixteen patients experienced Grade 4 toxicity. Twelve of these Grade 4 toxicities were hematologic. There were no treatment-related deaths. CONCLUSIONS: Cisplatin-gemcitabine combination chemotherapy has modest activity with an acceptable toxicity profile, as first line treatment for patients with malignant mesothelioma.

A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma.

PURPOSE: Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody-drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Le(y)) antigen, conjugated to doxorubicin. Le(y) is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Le(y)-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients. EXPERIMENTAL DESIGN: Sixty-two patients with recurrent or metastatic NSCLC expressing Le(y), one or two prior chemotherapy regimens, and PS< or =2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life. RESULTS: Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A. CONCLUSIONS: SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.

Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06.

PURPOSE: The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma. PATIENTS AND METHODS: Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV. RESULTS: Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v > or = 60 years), stage, or number of involved nodes (none v one to three v > or = four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV. CONCLUSION: UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

Gemcitabine-based therapy in pancreas cancer: gemcitabine-docetaxel and other novel combinations.

Since its approval in 1998 by the Food and Drug Administration, gemcitabine has rapidly become accepted as a standard part of palliative therapy for patients with advanced pancreatic cancer. It has modest activity when used as a single agent, and this has led to numerous studies combining it with other active agents, including cytotoxic as well as biologic and targeted therapies. Numerous Phase II studies suggest that the combinations may have greater activity than single agent therapy. However, randomized trials concerning this are still in progress. In the current article, a variety of gemcitabine-based novel combinations showing promising activity are reviewed.

Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma.

PURPOSE: To assess the efficacy and toxicity of combination therapy with gemcitabine and docetaxel in patients with unresectable pancreatic carcinoma. PATIENTS AND METHODS: Thirty-four patients with unresectable stage III, IVA, and IVB pancreatic carcinoma were eligible for this study. The first 18 patients received gemcitabine 800 mg/m2 intravenously (i.v.) on days 1, 8, and 15 and docetaxel 75 mg/m2 i.v. on day 1, repeated every 28 days. Due to a high incidence of myelosuppression in this first group, the treatment schedule was modified in the remaining patients to gemcitabine 1,000 mg/m2 i.v. and docetaxel 40 mg/m2 i.v. on days 1 and 8 of a 21-day schedule. The primary study endpoints were objective response rate and duration of survival. RESULTS: Ten of 33 evaluable patients achieved a partial response, for an overall response rate of 30.3% (95% CI, 16.21%-48.87%). Partial responses noted in the pancreas and a variety of metastatic sites were maintained for 4 to 12 months (median 6 months). Twelve additional patients (36%) experienced stable disease. The median time to progression was 6 months, and median survival was 10.5 months. The toxicity profile of the modified gemcitabine/docetaxel schedule was more favorable than that associated with the initial regimen, particularly with respect to hematologic toxicity. CONCLUSION: The response and survival data reported here for combination therapy with gemcitabine and docetaxel are encouraging given the poor prognosis associated with unresectable pancreatic cancer. These data suggest that gemcitabine plus docetaxel may be more effective than either agent alone in the treatment of pancreatic cancer and warrants further study.