Proton or photon? Comparative survival and toxicity outcomes in lung cancer radiotherapy: A systematic review and meta-analysis.

Abstract

e20048 Background: Radiotherapy (RT) is a cornerstone in non-small cell lung cancer (NSCLC) management. Conventional photon-based RT uses high-energy X-rays to induce DNA damage in tumor cells but inevitably exposes surrounding normal tissue. Proton beam RT offers more conformal dose delivery, potentially decreasing toxicity, yet its clinical superiority remains uncertain. Methods: Pubmed, MEDLINE, and Embase were systematically searched for observational studies comparing both modalities. Random-effects meta-analysis was used to pool risk and hazard ratios (RR/HR) for toxicity, along with 95% CIs and I² for heterogeneity. The study is registered in PROSPERO (CRD420261288838). Results: A total of 7 observational studies with a pooled population of 246,267 individuals were considered, out of which 245,216 received Photon RT and 1,051 received Proton RT. 5 studies of locally advanced/Stage II-III NSCLC were pooled for OS, demonstrating a non-significant trend favoring proton therapy (HR 0.79, 95% CI 0.51-1.23; P = 0.29; I² = 60%). Two studies of early-stage/Stage I NSCLC treated with SBRT showed no significant OS benefit on the pooled analysis (HR 0.70, 95% CI 0.32-1.55; P = 0.38; I² = 85%). In centrally located early-stage NSCLC treated with SBRT, Proton RT showed comparatively less toxicity (RR 0.32, 95% CI 0.14-0.74; P = 0.008). Other toxicity endpoints are presented in table 1. Photon RT has been the standard for lung cancer for decades because of its proven tumor control and acceptable toxicity. Our pooled analysis shows that proton therapy achieves similar OS and major toxicity outcomes, aligned with prior institutional and database studies that failed to demonstrate consistent superiority of protons in unselected populations. This equivalence is biologically plausible: both the Bragg peak and reduced exit dose may benefit from this, but this benefit can be diluted by motion uncertainty, range errors, and conservative planning margins. Therefore, routine replacement of photons is not supported; however, protons remain justified in anatomically high-risk settings where normal tissue sparing becomes clinically decisive. Conclusions: Proton therapy achieves survival and toxicity outcomes comparable to photon RT in NSCLC, supporting its role as a targeted option for selected high-risk cases rather than a universal replacement. Keywords: Proton, Photon, Radiotherapy, Lung cancer. Other toxicity endpoints. Outcome Grade Effect (RR, 95% CI) p-value I² Severe pneumonitis ≥ 3 1.29 (0.69-2.41) 0.43 0% Severe esophagitis ≥ 3 1.39 (0.44-4.32) 0.57 0% Cardiotoxicity ≥ 3 0.67 (0.19-2.30) 0.52 3% Pneumonitis ≥ 2 0.79 (0.44-1.41) 0.43 61%