Accelerated hypofractionated radiotherapy for locally-advanced non-small cell lung cancer: A systematic review from the International Association for the Study of Lung Cancer (IASLC) Advanced Radiation Technology (ART) Subcommittee

Accelerated hypofractionated radiotherapy has gained increasing interest for locally-advanced non-small cell lung cancer (NSCLC), as it can potentially increase radiobiologically effective (RBE) dose and reduce healthcare resource utilization. However, there is sparse prospective evidence supporting routine use of accelerated hypofractionation with or without concurrent chemotherapy. For this reason, the International Association for the Study of Lung Cancer (IASLC) Advanced Radiation Technology (ART) Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally-advanced NSCLC. A systematic search was conducted on Ovid MEDLINE, Ovid Embase, Wiley Cochrane Library, and ClinicalTrials.gov for English publications from 2010 to 2024 for prospective clinical trials and registries investigating accelerated hypofractionated radiotherapy defined as >2 Gy delivered over 10-25 fractions for non-metastatic locally-advanced (Stage III) NSCLC. There were 33 prospective studies identified that met criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were 6 prospective registries, 7 Phase 1-2 trials, and 1 Phase 3 randomized clinical trial (RCT), with a median dose of 60 Gy delivered in a median of 16 fractions, median progression free survival 6.4-25 months, median survival 6-34 months, and 0-8% severe grade ≥ 3 esophagitis. There were 19 studies evaluating accelerated hypofractionated chemoradiation with platinum doublet-based chemotherapy as the most common concurrent regimen. Of these accelerated hypofractionated chemoradiation studies, there were 18 Phase 1-2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median PFS 10-25 months, median survival 13-38 months, grade ≥ 3 esophagitis 0-23.5% and grade ≥ pneumonitis 0-11.8%. Despite the increasing use of accelerated hypofractionation for locally-advanced NSCLC, the supporting randomized evidence remains sparse. Only one RCT comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not demonstrate the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy approached with caution, utilizing advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should