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Extrapleural pneumonectomy (EPP) and adjuvant high-dose radiation therapy (RT) are associated with a median survival of 3 years in early-stage malignant pleural mesothelioma (MPM) but of less than 1 year in locally advanced disease. Although local control after EPP and RT is excellent, most patients die of distant metastases. We designed this clinical trial to test the feasibility of induction chemotherapy followed by EPP and RT in locally advanced MPM with the ultimate aim of improving survival.Patients with MPM and stage III or IV disease were eligible. Induction therapy was four cycles of gemcitabine and cisplatin. Patients without disease progression by computed tomography underwent EPP followed by adjuvant hemithoracic RT (54 cGy).From January 2002 to January 2004, 21 patients (17 men, four women; median age 60 years) were entered into the study. Histology was epithelioid in 14 patients and mixed or sarcomatoid five patients. Pretreatment disease stage was III in 13 patients and IV in six patients. Nineteen patients received induction chemotherapy. Response to induction therapy was complete in zero patients, partial in five patients, stable disease in six patients, and progression of disease in eight patients. Eight of nine patients undergoing surgical exploration had EPP. The median survival of all patients was 19 months. Patients who had an EPP had a median survival of 33.5 months. Patients with unresectable tumors had a median survival of 9 months (p = 0.01).Induction chemotherapy with gemcitabine and cisplatin followed by EPP and adjuvant RT for locally advanced MPM is feasible and leads to a better median overall survival than that previously reported with EPP and RT alone.