Safety of neoadjuvant radiotherapy or chemoradiotherapy combined with immunotherapy across solid tumors: Systematic review and meta-analysis protocol.

objectiveThe aim of this systematic review and meta-analysis is to evaluate whether neoadjuvant radiotherapy or chemoradiotherapy, combined with immune checkpoint inhibitors for adults with resectable solid tumors, increases the risk of severe treatment-related toxicity and organ-specific adverse events compared with radiotherapy or chemoradiotherapy alone.

methodsA systematic review and meta-analysis will be performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We will identify eligible studies published in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from January 2015 through March 2026. Clinical trial registries and major oncology conference proceedings will be searched, and references of included studies and relevant prior systematic reviews will be reviewed. Eligible studies will include randomized and observational cohorts of adults with resectable solid tumors receiving neoadjuvant radiotherapy or chemoradiotherapy combined with immune checkpoint inhibitors and reporting at least one prespecified safety outcome. Outcomes of interest include grade ≥ 3 treatment-related adverse events, grade ≥ 3 immune-related adverse events (overall and by organ system), treatment discontinuation, treatment-related death, requirement for systemic immunosuppression, radiotherapy site toxicities, and 90-day perioperative complications after surgery. Where appropriate, comparative data will be pooled using random-effects models and explored in subgroup analyses by tumor site, fractionation approach, and timing of immune checkpoint inhibitor delivery relative to radiotherapy. The protocol has been registered on the International Prospective Register for Systematic Reviews (PROSPERO CRD420261322883). DISCUSSION: Neoadjuvant radiotherapy and chemoradiotherapy are established components of curative-intent care across multiple solid tumors, and immune checkpoint inhibitors are increasingly used perioperatively. However, safety data for combined neoadjuvant radio-immunotherapy are fragmented across tumor sites and treatment schedules, limiting clear estimates of severe and organ-specific toxicity. This study will synthesize the available evidence on toxicity and perioperative complications and clarify safety risks, identify settings where toxicity may be concentrated, and highlight evidence gaps that should be addressed in future prospective comparative trials.