{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:44:04Z","timestamp":1785545044808,"version":"3.56.0"},"reference-count":32,"publisher":"JMIR Publications Inc.","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JMIR Res Protoc"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Cholangiocarcinoma is an aggressive biliary tract malignancy with poor long-term survival and high recurrence rates even after apparently curative surgery. Although postoperative systemic therapy is incorporated into contemporary management, the role of neoadjuvant therapy remains uncertain because the available evidence is heterogeneous and largely observational and often mixes initially resectable and initially unresectable disease.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n This protocol describes a systematic review and meta-analysis that will evaluate the safety and efficacy of neoadjuvant therapy followed by curative-intent surgery or liver transplantation in adults with cholangiocarcinoma. The review will address 2 clinically distinct pathways: initially resectable disease, in which neoadjuvant therapy is intended to improve oncological outcomes, and initially unresectable disease, in which treatment is intended to downstage disease or bridge patients to potentially curative surgery or transplantation.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The protocol has been prepared in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) 2015 statement and registered in PROSPERO. We will include randomized controlled trials and comparative nonrandomized studies evaluating neoadjuvant chemotherapy, chemoradiotherapy, immunotherapy, targeted therapy, or other preoperative antitumor therapy followed by curative-intent surgery or transplantation vs upfront surgery without preoperative systemic therapy. Single-arm studies, case reports, case series, and purely palliative cohorts will be excluded. The primary outcome will be overall survival analyzed as a time-to-event outcome using hazard ratios. Secondary outcomes will include recurrence-free survival, R0 resection, pathologic or radiologic complete response, conversion to operability among initially unresectable cohorts, and postoperative morbidity and mortality. Two reviewers will independently screen studies, extract data, and assess risk of bias using version 2 of the Cochrane risk-of-bias tool for randomized trials and the Risk of Bias in Nonrandomized Studies of Interventions tool for nonrandomized comparative studies. Random-effects meta-analysis; subgroup analyses; sensitivity analyses; assessment of reporting bias; and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty assessment will be undertaken where appropriate.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Database searches were completed on February 27, 2026. Title and abstract screening and full-text eligibility assessment were completed in March 2026. Data extraction commenced in April 2026. Meta-analysis is scheduled for May 2026, risk-of-bias and GRADE assessments are scheduled for June 2026, final manuscript preparation is scheduled for August 2026, and submission of the completed systematic review manuscript is scheduled for September 2026.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n This review will provide a methodologically explicit synthesis of comparative evidence on neoadjuvant therapy in cholangiocarcinoma while prespecifying separate analyses for initially resectable and initially unresectable disease. The findings are expected to inform future trial design, interpretation of emerging comparative evidence, and clinical decision-making in a setting where treatment intent varies substantially by resectability status.<\/jats:p>\n <\/jats:sec>","DOI":"10.2196\/84912","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T07:20:07Z","timestamp":1776756007000},"page":"e84912-e84912","source":"Crossref","is-referenced-by-count":0,"title":["Safety and Efficacy of Neoadjuvant Therapy in Cholangiocarcinoma: Protocol for a Systematic Review and Meta-Analysis"],"prefix":"10.2196","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-5295","authenticated-orcid":false,"given":"Saikat","family":"Mandal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-2569","authenticated-orcid":false,"given":"Arkadeep","family":"Dhali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2839-5158","authenticated-orcid":false,"given":"Manideepa","family":"Maji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh Vasan","family":"Venkatachalapathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amardeep","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanwant","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-4830","authenticated-orcid":false,"given":"Guruprasad","family":"Aithal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1010","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"issue":"3","key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100983","article-title":"Cholangiocarcinoma across England: temporal changes in incidence, survival and routes to diagnosis by region and level of socioeconomic deprivation","volume":"6","author":"Tataru","journal-title":"JHEP Rep"},{"issue":"9","key":"R2","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: the next horizon in mechanisms and management","volume":"17","author":"Banales","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"9","key":"R3","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/nrgastro.2011.131","article-title":"Clinical diagnosis and staging of cholangiocarcinoma","volume":"8","author":"Blechacz","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"5","key":"R4","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.gie.2013.09.015","article-title":"Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis","volume":"79","author":"Trikudanathan","journal-title":"Gastrointest Endosc"},{"issue":"9","key":"R5","doi-asserted-by":"publisher","first-page":"2314","DOI":"10.1007\/s10620-014-3124-4","article-title":"Evaluation of endoscopic transpapillary brushing cytology for the diagnosis of bile duct cancer based on the histopathologic findings","volume":"59","author":"Sasaki","journal-title":"Dig Dis Sci"},{"issue":"2","key":"R6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020362","article-title":"Treatment of intrahepatic cholangiocarcinoma-a multidisciplinary approach","volume":"14","author":"Krenzien","journal-title":"Cancers (Basel)"},{"issue":"7","key":"R7","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1080\/17474124.2018.1489229","article-title":"Challenges of surgical management of intrahepatic cholangiocarcinoma","volume":"12","author":"Squires","journal-title":"Expert Rev Gastroenterol Hepatol"},{"issue":"6","key":"R8","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1245\/s10434-010-0985-4","article-title":"The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM","volume":"17","author":"Edge","journal-title":"Ann Surg Oncol"},{"issue":"9","key":"R9","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1001\/jamasurg.2020.1973","article-title":"Very early recurrence after liver resection for intrahepatic cholangiocarcinoma: considering alternative treatment approaches","volume":"155","author":"Tsilimigras","journal-title":"JAMA Surg"},{"issue":"2","key":"R10","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.annonc.2022.10.506","article-title":"Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Vogel","journal-title":"Ann Oncol"},{"issue":"12","key":"R11","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1200\/JCO.18.02178","article-title":"Adjuvant therapy for resected biliary tract cancer: ASCO Clinical Practice Guidelines","volume":"37","author":"Shroff","journal-title":"J Clin Oncol"},{"issue":"7","key":"R12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement","volume":"6","author":"Moher","journal-title":"PLoS Med"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","journal-title":"BMJ"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","journal-title":"BMJ"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2018.01.012","article-title":"GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence","volume":"111","author":"Sch\u00fcnemann","journal-title":"J Clin Epidemiol"},{"issue":"24","key":"R16","doi-asserted-by":"publisher","first-page":"2815","DOI":"10.1002\/(SICI)1097-0258(19981230)17:24<2815::AID-SIM110>3.0.CO;2-8","article-title":"Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints","volume":"17","author":"Parmar","journal-title":"Statist Med"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1186\/1745-6215-8-16","article-title":"Practical methods for incorporating summary time-to-event data into meta-analysis","volume":"8","author":"Tierney","journal-title":"Trials"},{"key":"R18","doi-asserted-by":"publisher","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":"Wan","journal-title":"BMC Med Res Methodol"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-5-13","article-title":"Estimating the mean and variance from the median, range, and the size of a sample","volume":"5","author":"Hozo","journal-title":"BMC Med Res Methodol"},{"issue":"3","key":"R20","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","journal-title":"Control Clin Trials"},{"issue":"7109","key":"R21","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","journal-title":"BMJ"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-076754","article-title":"ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis","volume":"383","author":"Page","journal-title":"BMJ"},{"key":"R23","unstructured":"Review Manager (RevMan), version 7.12.0. The Cochrane Collaboration. URL: https:\/\/www.cochrane.org\/authors\/handbooks-and-manuals\/style-manual\/references\/reference-types\/software [Accessed 25-05-2025]"},{"key":"R24","unstructured":"Deeks JJ Higgins JP Li T et al. Analysing data and undertaking meta-analyses. In: Higgins JP Thomas J Chandler J Cumpston M Li T Page MJ Welch VA , editors. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons; 2024:492-539. ISBN: 9781119536628"},{"key":"R25","doi-asserted-by":"crossref","unstructured":"Higgins JP Thomas J Chandler J et al. Cochrane Handbook for Systematic Reviews of Interventions. Vol 4. John Wiley & Sons; 2019. ISBN: 9781119536604","DOI":"10.1002\/9781119536604"},{"issue":"1","key":"R26","doi-asserted-by":"publisher","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":"Moher","journal-title":"Syst Rev"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation","volume":"350","author":"Shamseer","journal-title":"BMJ"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.975136","article-title":"The role of neo-adjuvant therapy in cholangiocarcinoma: a systematic review","volume":"12","author":"Cremen","journal-title":"Front Oncol"},{"issue":"1","key":"R29","doi-asserted-by":"publisher","DOI":"10.1186\/s12876-023-02754-y","article-title":"Efficacy and safety comparison of neoadjuvant chemotherapy followed by surgery and upfront surgery for treating intrahepatic cholangiocarcinoma: a systematic review and meta-analysis","volume":"23","author":"Yang","journal-title":"BMC Gastroenterol"},{"issue":"16_suppl","key":"R30","doi-asserted-by":"publisher","first-page":"4008","DOI":"10.1200\/JCO.2025.43.16_suppl.4008","article-title":"Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone followed adjuvant therapy in biliary tract cancer: final results from the phase III AIO\/CALGP\/ACO-GAIN-Trial","volume":"43","author":"Goetze","journal-title":"J Clin Oncol"},{"key":"R31","unstructured":"Boleslawski E Piedvache C Boudjema K et al. Should liver transplantation be considered for resectable perihilar cholangiocarcinoma? Preliminary results from the TRANSPHIL French randomized controlled trial. Presented at: Proceedings of the 2025 EASL Liver Cancer Summit; Feb 20-22, 2025; Paris, France. URL: https:\/\/easl.eu\/wp-content\/uploads\/2025\/02\/EASL_LCS_2025_abstract_book.pdf [Accessed 25-05-2025]"},{"issue":"10","key":"R32","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1056\/NEJMoa2513918","article-title":"Neoadjuvant GOLP in resectable high-risk intrahepatic cholangiocarcinoma","volume":"394","author":"Shi","journal-title":"N Engl J Med"}],"container-title":["JMIR Research Protocols"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.researchprotocols.org\/2026\/1\/e84912","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:25:54Z","timestamp":1785536754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchprotocols.org\/2026\/1\/e84912"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":32,"URL":"https:\/\/doi.org\/10.2196\/84912","relation":{},"ISSN":["1929-0748"],"issn-type":[{"value":"1929-0748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"article-number":"v15i3e84912"}}