Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial)

Abstract

Purpose: We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM).

Methods: Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT.

Results: Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %.

Conclusion: This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory.

Keywords: Clinical trials; Mesothelioma; Pleural disease; Thoracic surgery.

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) diagram of registered patients. Of 42 registered patients, 33 underwent surgery. Three patients underwent exploratory thoracotomy because of unexpected extensive disease, and the remaining 30 completed extrapleural pneumonectomy (EPP) achieved macroscopic complete resection (MCR). Nineteen patients who underwent EPP started radiotherapy (RT), which was completed by 17

Fig. 2

Survival. a Kaplan–Meier analysis of the overall survival of 42 intent-to-treat (ITT) patients [median 19.9 months; 95 % confidence interval (CI) 14.2–27.3 months]. b Relapse-free survival (RFS) of extrapleural pneumonectomy (EPP) patients. Median RFS of patients who completed EPP with macroscopic complete resection (MCR) was 11.0 months (95 % CI 2.2 %–31.5 % months). RFS rate 2 years after surgery was 57.6 %

Fig. 3

Comparison of Kaplan–Meier overall survival analyses of extrapleural pneumonectomy (EPP) versus non-EPP patients. No significant difference was observed (median 22.7 months for EPP patients vs. 17.1 months for non-EPP patients)

Fig. 4

Significantly longer survival was observed for patients who completed trimodality therapy (TMT) (n = 17) in comparison with patients who completed extrapleural pneumonectomy (EPP) but not TMT (n = 13)