Prospective Feasibility and Phase 1/2 Trial of Preoperative Proton Beam Therapy With Concurrent Chemotherapy for Resectable Stage IIIA or Superior Sulcus Non-Small Cell Lung Cancer

Abstract

This is the first prospective clinical trial (NCTXXXX) evaluating proton beam therapy (PBT) with concurrent chemotherapy as part of trimodality management for resectable stage IIIA or superior sulcus non-small cell lung cancer (NSCLC). The starting PBT dose level was 50.4 Gy in 1.8 Gy fractions (feasibility study), followed by sequential dose escalation to determine maximum tolerated dose (MTD) of PBT based on dose-limiting toxicities (DLTs) (phase I/II study). DLTs were defined as 30-day postoperative mortality, grade ≥4 hematologic toxicity requiring >14-day treatment breaks, or any grade ≥3 non-hematologic/esophagitis/pneumonitis toxicities attributable to PBT. Primary outcomes included feasibility, MTD, and pathologic complete response (pCR) rate. Twenty patients underwent neoadjuvant PBT and chemotherapy, of which 19 subsequently underwent surgery. There were 13 patients in the feasibility study (at 50.4 Gy) and 6 in the phase I/II study (at 59.4 Gy). The trial closed early due to slow accrual prior to reaching the MTD. Treatment was deemed feasible. There were no DLTs, including no post-operative deaths within 30 days. Two patients (10%) experienced PBT-related acute grade 3 adverse events (post-operative atrial fibrillation and esophagitis/dysphagia); no grade 4-5 acute non-hematologic adverse events were noted. Overall and nodal pCR rates were 5/19 (26%) and 8/18 (44%), respectively; nodal pCR was 4/13 (31%) at 50.4 Gy versus 4/5 (80%) at 59.4 Gy (p=0.12). Median follow-up was 8.5 years. Median and 5-year progression-free survival were 1.8 years and 25%, and median and 5-year overall survival were 3.6 years and 40%, respectively. Eleven patients experienced disease failure, most with a distant component (10 of 11). Concurrent PBT and chemotherapy is feasible as part of trimodality management with favorable oncologic outcomes and low toxicity rates.