Proton Versus Photon Radiotherapy for Non-Small Cell Lung Cancer: Updated Evidence from a Systematic Review and Meta-Analysis.

Abstract

<h4>Purpose</h4>Proton beam therapy (PBT) offers superior dosimetric sparing of organs at risk compared to photon radiotherapy for non-small cell lung cancer (NSCLC); however, comparative clinical evidence regarding survival benefits remains conflicting. This systematic review and meta-analysis aimed to evaluate the clinical outcomes and toxicity profiles of PBT versus photon radiotherapy, with a specific focus on time-dependent survival patterns.<h4>Methods</h4>We searched PubMed, EMBASE, and Cochrane CENTRAL databases for comparative studies published up to 10 October 2025. Primary outcomes were overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS). Individual patient data (IPD) were reconstructed from Kaplan-Meier curves when hazard ratios (HRs) were not reported. Odds ratios (ORs) were calculated for survival at fixed time points (1, 3, and 5 years) and for toxicity endpoints.<h4>Results</h4>Seven studies comprising 244,604 patients were included, encompassing retrospective cohorts, multi-institutional datasets, and one randomized trial. In the overall pooled analysis, PBT showed no statistically significant superiority over photon radiotherapy for OS (HR = 0.91, 95% CI: 0.69-1.19, <i>p</i> = 0.483), PFS (HR = 1.09, 95% CI: 0.81-1.47, <i>p</i> = 0.572), or LPFS (HR = 0.89, 95% CI: 0.47-1.69, <i>p</i> = 0.732). Sensitivity and subgroup analyses restricted to Stage I and Stage I-II NSCLC similarly failed to demonstrate significant differences in survival outcomes. However, exploratory time point analysis utilizing ORs revealed a distinct temporal pattern: PBT was associated with improved odds of all-cause mortality at 1 year (OR = 0.60, 95% CI: 0.49-0.73, <i>p</i> < 0.001). This survival advantage dissipated over time, with no significant differences observed at 3 years or 5 years. Regarding safety, PBT did not significantly reduce the odds of grade ≥ 2 radiation pneumonitis (OR = 0.98, 95% CI: 0.41-2.33, <i>p</i> = 0.967) or grade ≥ 3 events (OR = 1.40, <i>p</i> = 0.540) compared to photons.<h4>Conclusions</h4>While long-term oncologic control appears comparable between proton and photon radiotherapy, exploratory analyses suggest that PBT is associated with improved odds of 1-year overall survival. This potential early benefit, observed in retrospective cohorts, likely reflects the mitigation of acute treatment-related mortality. These findings are hypothesis-generating and support the use of PBT for patients at high risk of toxicity and advocate for a model-based approach to patient selection.