A Phase I Trial of Surgical Resection and Intraoperative Hyperthermic Cisplatin and Gemcitabine for Pleural Mesothelioma

Introduction: The primary objective of this single-institution phase I clinical trial was to establish the maximum tolerated dose of gemcitabine added to cisplatin and delivered as heated intraoperative chemotherapy after resection of malignant pleural mesothelioma. Methods: The extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) treatment arms were based on investigators' assessment of patient fitness and potential for macroscopic complete resection. Previously established intracavitary dosing of cisplatin (range 175-225 mg/m(2)) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m(2) in 100-mg increments. Results: From 2007 to 2011, 141 patients were enrolled and 104 completed treatment. The median age of those completing treatment was 65 years (range 43-85 years), and 22 (21%) were female. In the EPP arm (n = 59), 31 patients (53%) had the epithelioid histologic type and the median radiographic tumor volume was 236 cm(3) (range 16-4285 cm(3)). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm(3) (range 6-1107 cm(3)). The operative mortality rate was 2%, and 35 and 22 serious adverse events were encountered among 27 patients (46%) and 16 patients (39%) in the EPP and P/D arms, respectively. Dose-limiting toxicity (grade 3 leukopenia) was observed in two patients who were receiving 1100 mg/m(2) of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m(2), in combination with 175 mg/m(2) of cisplatin. The median overall and recurrence-free survival times in treated patients were 20.3 and 10.7 months, respectively. Conclusions: Combination cisplatin and gemcitabine heated intraoperative chemotherapy can be administered safely and feasibly in the context of complete surgical resection of malignant pleural mesothelioma by EPP or P/D. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.