Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data

SIMPLE SUMMARY: The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) remains debatable due to inconclusive evidence. With a comprehensive systematic review involving not only randomized controlled trials (RCTs) but real-world cohorts and single-arm trials, we conducted two principled yet distinctive meta-analyses of the efficacy and safety differences between hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT), and hyperfractionated TRT (HyperTRT) regimens, especially in the modern era. In the one-stage meta-analysis using 8006 reconstructed individual patient data (IPD) from 53 studies, the overall survival (OS) rates were similar between the three fractionation regimens. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules. Results of the aggregated data (AD)-based network meta-analysis were consistent with those of the IPD analysis. The three TRT fraction regimens are acceptable options for LS-SCLC in the modern radiation era. ABSTRACT: The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93–1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90–1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91–1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.