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

J Thorac Oncol. 2018 Sep;13(9):1400-1409. doi: 10.1016/j.jtho.2018.04.032. Epub 2018 May 9.

Abstract

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/m2) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m2 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 cm3 (range 16-4285 cm3). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm3 (range 6-1107 cm3). 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/m2 of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m2, in combination with 175 mg/m2 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.

Keywords: Cisplatin; Gemcitabine; Heated chemotherapy; Mesothelioma; Pleurectomy; Pneumonectomy.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Cisplatin / therapeutic use*
  • Combined Modality Therapy
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Female
  • Humans
  • Hyperthermia, Induced / methods*
  • Male
  • Mesothelioma / drug therapy
  • Mesothelioma / pathology
  • Mesothelioma / surgery
  • Mesothelioma / therapy*
  • Middle Aged
  • Pleural Neoplasms / drug therapy
  • Pleural Neoplasms / pathology
  • Pleural Neoplasms / surgery
  • Pleural Neoplasms / therapy*
  • Prospective Studies

Substances

  • Antineoplastic Agents
  • Deoxycytidine
  • gemcitabine
  • Cisplatin