Marie T. Evans

Phase II Study of Vinorelbine in Patients With Malignant Pleural Mesothelioma

PURPOSE To evaluate the response rate and impact on quality of life of vinorelbine given as cycles of 30 mg/m(2) weekly for 6 weeks to patients with malignant pleural mesothelioma. PATIENTS AND METHODS Twenty-nine patients with histologically proven malignant pleural mesothelioma were enrolled (26 male patients and three female patients; median age, 58 years [range, 29 to 77 years]). Seventeen patients had epithelioid tumors, two had sarcomatoid tumors, and 10 had biphasic tumors. The International Mesothelioma Interest Group staging system was used: one patient had stage Ib disease, 10 had stage II disease, eight had stage III disease, and 10 had stage IV disease. Patients were treated with weekly injections of vinorelbine 30 mg/m(2). A cycle consisted of six weekly injections. The new guidelines to evaluate the response to treatment in solid tumors were used. Responses were measured by spiral computed tomography scan. RESULTS All twenty-nine patients had measurable disease and were assessed for response. There were seven partial responses (24% [95% confidence interval, 10% to 44%]), 16 patients had stable disease (55%), and six patients had disease progression on therapy (21%). The median number of vinorelbine injections was 12 (range, 2 to 30). Quality-of-life analyses showed a benefit for vinorelbine therapy. CONCLUSION Vinorelbine shows promise in the palliation of patients with malignant pleural mesothelioma. The relatively low toxicity of the drug suggests that trials of vinorelbine in combination with other agents should be feasible.

Statistical Validation of the EORTC Prognostic Model for Malignant Pleural Mesothelioma Based on Three Consecutive Phase II Trials

PURPOSE Malignant pleural mesothelioma (MPM) carries a poor prognosis due to chemoresistance. The European Organisation for Research and Treatment of Cancer (EORTC) prognostic model was reported to predict survival in MPM. Our retrospective analysis set out to test the validity of the model as a prognostic tool in patients treated in three phase II trials at St Bartholomews Hospital (London, United Kingdom) between 1999 and 2003. PATIENTS AND METHODS A total of 145 patients were treated in three phase II trials; vinorelbine (VIN; 70 patients), vinorelbine/oxaliplatin (VO; 26 patients), and irinotecan/cisplatin/mitomycin C (IPM; 49 patients). Two subgroups, high-risk and low-risk, were defined by EORTC prognostic score (EPS). EPS was determined by a five-parameter model incorporating age, sex, histology, probability of diagnosis, and leukocyte count. An EPS cutoff of less than 1.27 (low risk) or more than 1.27 (high risk) was used to stratify Kaplan-Meier survival curves. Each of the EPS variables exhibited either trends or significant stratification of overall survival (OS). RESULTS Multivariate analysis confirmed leukocyte count, Eastern Cooperative Oncology Group performance status, and sarcomatous histology as independent prognostic variables. EPS stratified OS in both individual and pooled trial datasets. No association between objective tumor response and EPS classification was identified by multinomial logistic regression. EPS stratified progression-free survival for the VO and IPM cohorts, but not for VIN. CONCLUSION This study validates the EPS system as a robust tool for stratifying small trials into low- and high-risk subgroups. EPS should facilitate patient selection and analysis in randomized clinical trials.

Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesothelioma

Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor.

A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma

A total of 29 previously untreated patients with histologically proven malignant pleural mesothelioma, with an ECOG score of < or = 2 and UICC stage I-II disease, were enrolled between May 1994 and October 1996. On days 1 and 2, 18 x 10(6) IU/day of rIL-2 was administered by continuous intravenous infusion, and 6 x 10(6) IU/day of rIL-2 by subcutaneous injection on days 5--20 inclusive of a 42-day cycle. Further treatment was administered if no radiological disease progression was demonstrated. A total of 29 patients were assessable for toxicity and 25 for response, and 49 cycles of IL-2 were administered with a median of one per patient (range, < 1-4). Toxicity included mild fever, nausea and vomiting, and skin rashes, < grade II. Three patients failed to complete one cycle of treatment because of toxicity and one died of disease before response evaluation. Two patients achieved a partial response (8%, 95% CI 1-26%) surviving 18.1 and 18.7 months from diagnosis. A total of 11 patients (44%, 95% CI 24-65%) with stable disease had a median survival of 13.6 months (range 6.5-33.8). The median survival was 8.6 months (range 3.7-34.5) for the 12 patients with progressive disease (48%, 95% CI 28-69%). This regimen of rIL-2 is well tolerated and shows limited activity in mesothelioma.

Identification of glucose transporter type 1 overexpression as a predictor of survival in patients with malignant pleural mesothelioma

7199 Background: Malignant pleural mesothelioma (MPM) is characterized by resistance to cytotoxic therapy dependent in part on apoptosis induction. Apoptosis and glycolysis are linked. The aim of this study was to determine the expression and prognostic significance of glucose transporter 1 (GLUT-1) in MPM. METHODS GLUT-1 was measured in 51 archival MPM specimens by immunohistochemistry. Placenta was used as a positive control with antibody diluent as a negative control. 36 MPM patients (pts) were previously treated in 3 consecutive phase II clinical trials at St Bartholomews Hospital (vinorelbine1 14 pts, vinorelbine/oxaliplatin 7 pts, irinotecan cisplatin mitomycin C 15 pts). GLUT-1 intensity and extent were scored in duplicate and impact on response rate (RR), progression free survival (PFS) and overall survival (OS) studied. Comparison was made with the EORTC prognostic score (EPS)2. RESULTS GLUT-1 was expressed in 12 specimens (23%). HIF-1α expression was observed in 79%. No association with between GLUT-1 and RR was observed (χ2 test p > 0.05). Trend to shorter PFS was observed in GLUT-1 positive pts. PFS was 4.4 months (95% confidence limits (CI) 0-11) compared to 6.9 months (95% CI 4.8-9.0, log rank statistic (LR) 0.9, p > 0.05). OS was worse in GLUT-1 positive MPM, 9.4 months (95% CI 4.9-14.8), compared to 14.2 months (95% CI 11.0-17.4, LR 4.2, p = 0.04). The EPS showed a trend to worse survival for poor risk patients with an OS of 12.5 months (95% CI 8.0-17.0) compared to good risk patients with an OS of 14.0 months (95% CI 2.1-25.8, LR 3.3 p = 0.07). High resolution, genome-wide array comparative genomic hybridisation studies are in progress investigating links between DNA copy number changes and glycolytic protein expression and will be presented. CONCLUSIONS GLUT-1 is overexpressed in some pts with MPM and predicts for poor clinical outcome at least as efficiently as the EORTC prognostic score 2. Identification of pts with GLUT-1 positive MPM at diagnosis should facilitate design and interpretation of clinical trials. References: 1. Steele JP et al J Clin Oncol 2000;18(23):3912-7 2. Curran D et al J Clin Oncol 1998;16(1):145-52 No significant financial relationships to disclose.