{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:14:06Z","timestamp":1788200046804,"version":"build-2803163510"},"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 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\u2009\u2265\u20093 treatment-related adverse events, grade\u2009\u2265\u20093 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0357205","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:24:43Z","timestamp":1788197083000},"page":"e0357205","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety of neoadjuvant radiotherapy or chemoradiotherapy combined with immunotherapy across solid tumors: Systematic review and meta-analysis protocol"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3556-4944","authenticated-orcid":true,"given":"Irtaza","family":"Tahir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4909-8112","authenticated-orcid":true,"given":"Susheen","family":"Mahmood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoo","family":"Aminnejad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Parvez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"pone.0357205.ref001","doi-asserted-by":"crossref","first-page":"1554499","DOI":"10.3389\/fimmu.2025.1554499","article-title":"Synergies between radiotherapy and immunotherapy: a systematic review from mechanism to clinical application","volume":"16","author":"J Jiang","year":"2025","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0357205.ref002","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13045-018-0647-8","article-title":"Abscopal effect of radiotherapy combined with immune checkpoint inhibitors","volume":"11","author":"Y Liu","year":"2018","journal-title":"J Hematol Oncol"},{"issue":"2","key":"pone.0357205.ref003","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nri.2016.107","article-title":"Immunogenic cell death in cancer and infectious disease","volume":"17","author":"L Galluzzi","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"pone.0357205.ref004","doi-asserted-by":"crossref","first-page":"1392499","DOI":"10.3389\/fimmu.2024.1392499","article-title":"The efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer patients: a systematic review","volume":"15","author":"L Yang","year":"2024","journal-title":"Front Immunol"},{"issue":"10467","key":"pone.0357205.ref005","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1016\/S0140-6736(24)01812-9","article-title":"Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial","volume":"404","author":"YM Mowery","year":"2024","journal-title":"Lancet"},{"issue":"12","key":"pone.0357205.ref006","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1158\/1078-0432.CCR-20-4443","article-title":"Neoadjuvant Chemoradiotherapy Combined with Atezolizumab for Resectable Esophageal Adenocarcinoma: A Single-arm Phase II Feasibility Trial (PERFECT)","volume":"27","author":"T van den Ende","year":"2021","journal-title":"Clin Cancer Res"},{"key":"pone.0357205.ref007","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ejca.2020.11.039","article-title":"Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1)","volume":"144","author":"C Li","year":"2021","journal-title":"Eur J Cancer"},{"issue":"1","key":"pone.0357205.ref008","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s13014-024-02489-4","article-title":"Respiratory adverse effects in patients treated with immune checkpoint inhibitors in combination with radiotherapy: a systematic review and meta-analysis","volume":"19","author":"Z Ma","year":"2024","journal-title":"Radiat Oncol"},{"key":"pone.0357205.ref009","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"MJ Page","year":"2021","journal-title":"BMJ"},{"issue":"1","key":"pone.0357205.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2046-4053-4-1","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement","volume":"4","author":"D Moher","year":"2015","journal-title":"Syst Rev"},{"key":"pone.0357205.ref011","unstructured":"National Cancer Institute. CTEP trial development and conduct: CTCAE legacy version mapping [Internet]. [cited 2025 Aug 27]. Available from: https:\/\/dctd.cancer.gov\/research\/ctep-trials\/trial-development"},{"issue":"2","key":"pone.0357205.ref012","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1097\/01.sla.0000133083.54934.ae","article-title":"Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey","volume":"240","author":"D Dindo","year":"2004","journal-title":"Ann Surg"},{"key":"pone.0357205.ref013","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1471-2288-14-135","article-title":"Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range","volume":"14","author":"X Wan","year":"2014","journal-title":"BMC Med Res Methodol"},{"issue":"1","key":"pone.0357205.ref014","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12874-018-0483-0","article-title":"Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review","volume":"18","author":"CJ Weir","year":"2018","journal-title":"BMC Med Res Methodol"},{"key":"pone.0357205.ref015","doi-asserted-by":"crossref","unstructured":"Sterne JAC, Savovi\u0107 J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials [Internet]. 2019 [cited 2026 May 5]. Available from: https:\/\/www.riskofbias.info\/welcome\/rob-2-0-tool","DOI":"10.1136\/bmj.l4898"},{"key":"pone.0357205.ref016","unstructured":"Sterne JAC, Higgins JPT. ROBINS-I V2 tool [Internet]. 2025 [cited 2026 May 5]. Available from: https:\/\/www.riskofbias.info\/welcome\/robins-i-v2"},{"issue":"1","key":"pone.0357205.ref017","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jrsm.1411","article-title":"Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments","volume":"12","author":"LA McGuinness","year":"2021","journal-title":"Res Synth Methods"},{"issue":"7650","key":"pone.0357205.ref018","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"GH Guyatt","year":"2008","journal-title":"BMJ"},{"key":"pone.0357205.ref019","unstructured":"Sch\u00fcnemann H, Bro\u017cek J, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations [Internet]. The GRADE Working Group. 2013 [cited 2025 Sep 5]. Available from: https:\/\/gradepro.org\/handbook\/"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357205","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:24:47Z","timestamp":1788197087000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357205"}},"subtitle":[],"editor":[{"given":"Satyajeet","family":"Rath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":19,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0357205","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}