This protocol describes a systematic review and meta-analysis designed to evaluate whether adding immune checkpoint inhibitors (ICIs) to neoadjuvant radiotherapy (nRT) or neoadjuvant chemoradiotherapy (nCRT) for adults with resectable solid tumors increases severe treatment-related toxicity or organ-specific adverse events compared with nRT/nCRT alone. The primary outcome is incidence of grade ≥3 treatment-related adverse events (trAEs). Secondary outcomes include grade ≥3 and any-grade immune-related adverse events (irAEs) by organ system, treatment discontinuation, treatment-related death, need for systemic immunosuppression, RT site toxicities, and perioperative complications. The review will follow PRISMA guidelines, search MEDLINE, Embase, and CENTRAL from January 2015 to March 31, 2026, include conference abstracts and trial registries, and pool comparative data using random-effects models where appropriate. The protocol is registered on PROSPERO (CRD420261322883).
Radiotherapy exerts local cytotoxic effects and notable immunomodulatory activity in the tumor microenvironment through antigen release, dendritic cell activation, and promotion of T-cell infiltration. When combined with ICIs (anti–PD-1, anti–PD-L1, anti–CTLA-4, or similar agents), these effects may be amplified, producing systemic antitumor immunity and, in some cases, abscopal responses. The addition of cytotoxic chemotherapy within nCRT may further increase immunogenic cell death and modulate suppressive immune populations, potentially enhancing synergy with ICIs.
Early clinical studies across multiple tumor types have suggested feasibility and promising pathologic responses when ICIs are added to standard nRT/nCRT regimens. Nonetheless, safety data remain fragmented across tumor sites and treatment schedules, and toxicity reporting practices vary with different CTCAE versions and event attributions. Organ-specific toxicities such as pneumonitis after thoracic RT or dermatitis with large-field RT are particular concerns when combining RT and ICIs.
A focused systematic review is needed to synthesize safety outcomes across cancer types and treatment approaches to determine whether combining ICIs with nRT/nCRT increases severe or organ-specific toxicities compared with nRT/nCRT alone. Clarifying risks by timing (concurrent vs sequential), fractionation, and tumor site will inform clinical decision-making and identify settings requiring prospective comparative study.
Research question: Among adults with resectable solid tumors, does nRT or nCRT combined with ICIs increase the risk of adverse events compared with nRT or nCRT alone?
Hypotheses:
This systematic review and meta-analysis will be conducted and reported according to PRISMA. The protocol has been prepared in line with PRISMA-P and registered on PROSPERO (CRD420261322883). Two reviewers will independently screen titles, abstracts, and full texts using Covidence; disagreements at title/abstract stage will default to inclusion, and full-text disagreements will be resolved by consensus or a third reviewer if needed.
Radiotherapy modalities eligible include external-beam techniques (3D-CRT, IMRT/VMAT, proton therapy, SBRT/SRS) directed at the intact primary tumor and/or regional nodes in the preoperative setting. Intraoperative brachytherapy alone and radiopharmaceutical therapies are excluded. Chemoradiotherapy denotes RT delivered concurrently with disease-specific cytotoxic chemotherapy (e.g., long-course rectal nCRT or CROSS regimen in esophageal cancer). ICIs eligible include agents targeting PD-1, PD-L1, CTLA-4, or LAG-3, administered concurrently with RT or in induction/consolidation schedules prior to surgery. Fractionation categories of interest are conventional, hypofractionated, short-course, and SBRT/SRS.
Comparator arms must consist of nRT or nCRT without immunotherapy, with clear preoperative intent and planned curative resection. Trials limited to adjuvant-only RT or non-surgical ablative RT without surgical intent will be excluded. For multi-arm or platform trials, pairwise comparisons will be extracted independently.
Primary outcome: Incidence of grade ≥3 treatment-related adverse events during the neoadjuvant period through 90 days postoperatively, assessed per CTCAE v3–v6 and treated as a binary event within each study.
Secondary outcomes: Grade ≥3 and any-grade irAEs attributed to ICI use (including pneumonitis, colitis, hepatitis, endocrinopathies, myocarditis, nephritis, neurologic events); treatment-related death (grade 5); treatment discontinuation; requirement for systemic steroids or other immunosuppression; radiation site–specific toxicities (e.g., esophagitis, proctitis, dermatitis); and perioperative complications reported within 30 or 90 days, preferably using Clavien–Dindo grading.
Databases to be searched are MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), limited to publications between January 2015 and March 31, 2026. No language restrictions will be applied. ClinicalTrials.gov and other trial registries will be searched for ongoing studies. Abstracts from major oncology conferences (ASCO, ASTRO, ESMO, AACR) will be screened to capture recent or unpublished reports. References of included studies and prior relevant systematic reviews will be hand-searched. The Medline search strategy is provided in a supplement to the protocol.
Two reviewers will independently screen records using web-based software (Covidence). Title and abstract screening discrepancies will default to inclusion for full-text review. Full-text disagreements will be resolved by consensus or adjudicated by a third reviewer.
Eligible studies include randomized and observational cohorts of adults with resectable solid tumors receiving nRT/nCRT with or without ICIs and reporting at least one prespecified safety outcome. The search period reflects the clinical adoption of ICIs in oncology and the emergence of neoadjuvant radio-immunotherapy studies after 2015.
Where comparative data permit, pooled estimates will be generated using random-effects meta-analysis. Subgroup analyses planned include tumor site, fractionation approach, and timing of ICI delivery relative to RT (concurrent vs sequential). The protocol acknowledges heterogeneity in toxicity reporting across CTCAE versions and attribution practices and anticipates exploring heterogeneity and robustness of findings.
The protocol is registered on PROSPERO (CRD420261322883). No specific funding was received for the work. The authors declare no competing interests. As a study protocol, no datasets were generated or analyzed; relevant data will be shared upon completion of the review.
Note: The source document ends partway through the eligibility section; further procedural details (data extraction fields, risk-of-bias assessment tools, specific meta-analytic statistical methods and thresholds) were not reported in the provided text.