Accelerated Hypofractionated Radiotherapy for Locally Advanced NSCLC: A Systematic Review From the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee

Introduction: Accelerated hypofractionated radiotherapy has gained increasing interest for locally advanced NSCLC, as it can potentially increase radiobiologically effective dose and reduce health care resource utilization. Nevertheless, 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 Advanced Radiation Technology Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally advanced NSCLC.

Methods: 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 more than 2 Gy delivered in 10 to 25 fractions for nonmetastatic locally advanced (stage III) NSCLC.

Results: There were 33 prospective studies identified that met the criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were six prospective registries, seven phase 1 to 2 trials, and one phase 3 randomized clinical trial, with a median dose of 60 Gy delivered in a median of 16 fractions, median progression-free survival of 6.4 to 25 months, median survival of 6 to 34 months, and 0% to 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 to 2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median progression-free survival of 10 to 25 months, median survival of 13 to 38 months, grade ≥3 esophagitis of 0% to 23.5%, and grade ≥3 pneumonitis of 0% to 11.8%.

Conclusions: Despite the increasing use of accelerated hypofractionation for locally advanced NSCLC, the supporting randomized evidence remains sparse. Only one randomized clinical trial comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not reveal the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy should be approached with caution, using advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should be carefully considered alongside other multidisciplinary options and be further investigated through prospective clinical trials.