Prospective Assessment of Proton Therapy for Malignant Pleural Mesothelioma

Abstract

Radiation therapy (RT) treatment for malignant pleural mesothelioma (MPM) is challenging due to the large treatment fields needed for both definitive and adjuvant RT following extrapleural pneumonectomy or lung-sparing surgery. Most published experiences to date report photon and electron outcomes. Proton therapy (PT) can offer substantial dose sparing to the lungs and other organs, which may improve the therapeutic ratio. Reports of PT for MPM are limited. We report our experience treating patients with MPM with definitive or adjuvant PT. We hypothesized that PT would achieve high local control with low pneumonitis and esophagitis rates. We reviewed all consecutive patients treated for MPM at our institution between 2011-2017 as part of a prospective registry study. We assessed disease control outcomes and CTCAEv4 acute and late toxicities. Nineteen patients treated to 21 PT courses were included. Patients were predominantly male (74%) and Caucasian (100%), with epithelioid (84%) histology and stage III-IV disease (89%). The median age at PT start was 68.4 years delivered at a median of 15.4 mo. (range 3.5-59.4 mo.) after MPM diagnosis. Most patients received pemetrexed and cisplatin or carboplatin prior to (n = 15) or during (n = 2) PT. Two patients received concurrent pemetrexed alone, and 1 received concurrent pembrolizumab (IT). PT was delivered as adjuvant treatment after lung-sparing extended pleurectomy decortication (n = 8), for gross progression on/after systemic therapy (n = 12), or as primary definitive concurrent therapy (n = 1). Median PT dose was 54 CGE in 2.0 CGE daily fractions (range, 50-75/1.8-2.6 CGE). At a median follow-up of 17.7 months after start of PT, local, regional, and distant control were 90%, 48%, and 14%, respectively. The median progression-free survival and overall survival (OS) were 5.1 months (95% CI 3.3-10.7 months) and 17.7 months (95% CI 7.2-30.4 months) from start of PT, respectively. The 6-, 12-, 18-, and 24- month OS rates were 84%, 68%, 47%, and 37%, respectively. Grade ≥3 toxicities included a bronchopleural fistula (n = 1, late, G4) and dyspnea (n = 1, acute, G3). Acute grade 2 toxicities included RT dermatitis (n = 8), dysphagia/esophagitis (n = 5), anorexia (n = 5), fatigue (n = 4), cough (n = 2), and dyspnea (n = 1). Late grade 2 toxicities included RT pneumonitis (n = 4, including 1 that received concurrent IT and 1 that received post-RT IT with a history of autoimmune disease). ECOG PS remained stable from before to after PT (mean 0.81 to 0.90). In the largest prospective registry experience of PT for MPM to date, PT achieved durable local control with toxicity that compares favorably with prior photon experiences. Thus, PT may offer safer integration of RT in multi-modality paradigms for MPM. Additional follow-up, patients, and study with IT agents are needed to further establish the long-term survival and toxicity profile of PT for MPM.