Over-modulated plan undermines prognosis of small cell lung cancer patients treated under free-breathing: analysis based on a multicenter, open-label, phase 3 trial

Objective: To investigate the clinical impact of plan complexity on local progression-free survival (LPFS) and overall survival (OS) in limited-stage small cell lung cancer (LS-SCLC) patients treated with hyper-fractionated radiotherapy. Methods: Partially based on a multicenter, open-label, phase 3 trial in China, this study included 209 treatment plans from 193 LS-SCLC patients of 7 institutions. Plan average beam area (PA), plan averaged beam modulation (PM) and monitor unit per Gy (MU/Gy) were calculated as indicators of plan complexity. Based on the statistical significance of these metrics and their correlation with survival time, cutoff values determined by the Youden's index were used to stratify patients into high complexity (HC) and low complexity (LC) groups. Kaplan-Meier analysis, Cox regression, and random survival forest (RSF) models were employed to analyze LPFS and OS. Propensity-score-matched pairs were generated to minimize bias in the baseline. Results: The median follow-up time for the selected patients was 28.77 (interquartile range 22.43–51.90) months. Variable importance and minimal depth methods based on RSF revealed the significant prognostic capability of PM. The 1-, 2-, and 3-year LPFS rates and OS rates in the PM-defined HC group were significantly lower than those in the LC group (P < 0.05). However, no significant difference was observed between the HC and LC groups using other definitions of plan complexity (all P > 0.05). Conclusions: Complex radiotherapy plan significantly reduced the LPFS and OS of limited-stage SCLC patients. PM should be optimized during the planning or evaluation to improve the clinical prognosis.