Toxicity Within 6 Months of Heterogeneous Fluorodeoxyglucose-Guided Radiotherapy Dose Escalation for Locally Advanced Non–Small Cell Lung Cancer in the Scandinavian Randomized Phase III NARLAL2 Trial

PURPOSE Radiation dose escalation for locally advanced non–small cell lung cancer (LA-NSCLC) has been challenged by toxicity concerns. The Scandinavian phase III multicenter dose-escalation trial NARLAL2 (ClinicalTrials.gov identifier: NCT02354274 ) used a novel approach to dose escalation: heterogeneous escalation driven by the fluorodeoxyglucose positron emission tomography–avid region, with strict normal tissue dose constraints. We report early toxicity within 6 months of random assignment. MATERIALS AND METHODS Patients were recruited from seven institutions in Scandinavia. Eligibility criteria included performance status 0-1, NSCLC stage IIB-IIIB, and feasibility of delivering 66 Gy/33 fraction treatment plan. Patients were randomly assigned between standard (66 Gy) and heterogeneously dose-escalated radiotherapy. Two treatment plans were made for each patient before random assignment with matched mean lung dose and V 20Gy , and strict dose constraints for all normal tissues. Toxicity was evaluated weekly during radiotherapy, and every 3 months after random assignment. Concurrent chemotherapy was cisplatin/carboplatin and Navelbine. RESULTS Between January 2015 and March 2023, 350 patients were randomly assigned. The as-treated analysis included 178 patients in the standard and 172 in dose-escalated (mean tumor dose 88 Gy) arms. Median gross tumor and planning target volumes were, respectively, 54 cm 3 and 321 cm 3 (standard arm) and 61 cm 3 and 339 cm 3 (escalated arm). No difference in early toxicity between the two arms was observed. Grade 2 esophagitis during radiotherapy was 28.1% and 25.6%, grade 3 esophagitis 7.3% and 4.1%, grade 2 pneumonitis 15.7% and 20.3%, and grade 3 pneumonitis 3.9% and 5.8% in standard and escalated arms, respectively. For both arms, the maximum grade of early toxicity aggregated over all toxicities was 35% and 1% for grades ≥3 and 5, respectively. Four patients died from potential treatment-related toxicity. CONCLUSION Heterogeneous dose escalation did not increase early toxicity despite delivery of 88 Gy mean dose to the primary tumor, demonstrating this as an attractive strategy for LA-NSCLC radiotherapy dose escalation.