{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T14:09:19Z","timestamp":1775830159284,"version":"3.50.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Gastrointest Canc"],"DOI":"10.1007\/s12029-026-01460-8","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:35:00Z","timestamp":1775828100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-World Study of anti-PD-1 Combined with Regorafenib and Raltitrexed as Third-Line Therapy in Colorectal Cancer"],"prefix":"10.1007","volume":"57","author":[{"given":"Yi","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laixiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinxiu","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinbo","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honglian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiqi","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiehao","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhe","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2776-1266","authenticated-orcid":false,"given":"Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"1460_CR1","doi-asserted-by":"crossref","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A, Cancer statistics. 2023. CA Cancer J Clin. 2023;73(1):17\u201348.","DOI":"10.3322\/caac.21763"},{"key":"1460_CR2","doi-asserted-by":"crossref","unstructured":"Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A et al. Colorectal cancer statistics, 2017.\u00a0CA Cancer J Clin. 2017;67(3):177\u201393.","DOI":"10.3322\/caac.21395"},{"issue":"Suppl 5","key":"1460_CR3","doi-asserted-by":"publisher","first-page":"v93","DOI":"10.1093\/annonc\/mdq222","volume":"21","author":"E Van Cutsem","year":"2010","unstructured":"Van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol May. 2010;21(Suppl 5):v93\u201397.","journal-title":"Ann Oncol May"},{"issue":"11","key":"1460_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70424-2","volume":"13","author":"G Ku","year":"2012","unstructured":"Ku G, Tan IB, Yau T, Boku N, Laohavinij S, Cheng A-L, et al. Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012. Lancet Oncol. 2012;13(11):e470-481.","journal-title":"Lancet Oncol"},{"issue":"9863","key":"1460_CR5","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","volume":"26","author":"A Grothey","year":"2013","unstructured":"Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet January. 2013;26(9863):303\u201312.","journal-title":"Lancet January"},{"issue":"20","key":"1460_CR6","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1056\/NEJMoa1414325","volume":"14","author":"RJ Mayer","year":"2015","unstructured":"Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. May 2015;14(20):1909\u201319.","journal-title":"N Engl J Med"},{"issue":"5","key":"1460_CR7","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1634\/theoncologist.2018-0901","volume":"24","author":"Y Chen","year":"2019","unstructured":"Chen Y, Wu J, Cheng K, Li Z-P, Luo D-Y, Qiu M, et al. S-1 plus Raltitrexed for Refractory Metastatic Colorectal Cancer: A Phase II Trial. Oncologist May. 2019;24(5):591\u2013e165.","journal-title":"Oncologist May"},{"issue":"24","key":"1460_CR8","doi-asserted-by":"publisher","first-page":"2486","DOI":"10.1001\/jama.2018.7855","volume":"26","author":"J Li","year":"2018","unstructured":"Li J, Qin S, Xu R-H, Shen L, Xu J, Bai Y, et al. Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial. JAMA June. 2018;26(24):2486\u201396.","journal-title":"JAMA June"},{"issue":"26","key":"1460_CR9","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","volume":"25","author":"DT Le","year":"2015","unstructured":"Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. June 2015;25(26):2509\u201320.","journal-title":"N Engl J Med"},{"issue":"1","key":"1460_CR10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1200\/JCO.19.02107","volume":"1","author":"DT Le","year":"2020","unstructured":"Le DT, Kim TW, Van Cutsem E, Geva R, J\u00e4ger D, Hara H, et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High\/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. January 2020;1(1):11\u20139.","journal-title":"J Clin Oncol"},{"issue":"5","key":"1460_CR11","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/S1470-2045(22)00197-8","volume":"23","author":"LAJ Diaz","year":"2022","unstructured":"Diaz LAJ, Shiu K-K, Kim T-W, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659\u201370.","journal-title":"Lancet Oncol"},{"issue":"9","key":"1460_CR12","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/S1470-2045(17)30422-9","volume":"18","author":"MJ Overman","year":"2017","unstructured":"Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol September. 2017;18(9):1182\u201391.","journal-title":"Lancet Oncol September"},{"issue":"6","key":"1460_CR13","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1158\/2159-8290.CD-17-1327","volume":"8","author":"CS Grasso","year":"2018","unstructured":"Grasso CS, Giannakis M, Wells DK, Hamada T, Mu XJ, Quist M, et al. Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov June. 2018;8(6):730\u201349.","journal-title":"Cancer Discov June"},{"issue":"7","key":"1460_CR14","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1158\/1535-7163.MCT-12-1162","volume":"12","author":"L Abou-Elkacem","year":"2013","unstructured":"Abou-Elkacem L, Arns S, Brix G, Gremse F, Zopf D, Kiessling F, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12(7):1322\u201331.","journal-title":"Mol Cancer Ther"},{"issue":"1","key":"1460_CR15","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1186\/s13046-021-02043-0","volume":"13","author":"D Doleschel","year":"2021","unstructured":"Doleschel D, Hoff S, Koletnik S, Rix A, Zopf D, Kiessling F, et al. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. J Exp Clin Cancer Res September. 2021;13(1):288.","journal-title":"J Exp Clin Cancer Res September"},{"issue":"18","key":"1460_CR16","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1200\/JCO.19.03296","volume":"20","author":"S Fukuoka","year":"2020","unstructured":"Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol June. 2020;20(18):2053\u201361.","journal-title":"J Clin Oncol June"},{"issue":"9","key":"1460_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100383","volume":"2","author":"F Wang","year":"2021","unstructured":"Wang F, He M-M, Yao Y-C, Zhao X, Wang Z-Q, Jin Y, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib\/II clinical trial and gut microbiome analysis. Cell Rep Med. 2021;2(9):100383.","journal-title":"Cell Rep Med"},{"issue":"3","key":"1460_CR18","doi-asserted-by":"publisher","first-page":"423","DOI":"10.2165\/00003495-199855030-00012","volume":"55","author":"NS Gunasekara","year":"1998","unstructured":"Gunasekara NS, Faulds D. Raltitrexed. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs. 1998;55(3):423\u201335.","journal-title":"Drugs"},{"issue":"2","key":"1460_CR19","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","volume":"45","author":"EA Eisenhauer","year":"2009","unstructured":"Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228\u201347.","journal-title":"Eur J Cancer"},{"issue":"23","key":"1460_CR20","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","volume":"3","author":"T Andr\u00e9","year":"2020","unstructured":"Andr\u00e9 T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. December 2020;3(23):2207\u201318.","journal-title":"N Engl J Med"},{"issue":"2","key":"1460_CR21","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/sj.bjc.6604867","volume":"27","author":"M Koopman","year":"2009","unstructured":"Koopman M, Kortman GAM, Mekenkamp L, Ligtenberg MJL, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer January. 2009;27(2):266\u201373.","journal-title":"Br J Cancer January"},{"issue":"1","key":"1460_CR22","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s13045-022-01294-4","volume":"16","author":"J Weng","year":"2022","unstructured":"Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, et al. Exploring immunotherapy in colorectal cancer. J Hematol Oncol July. 2022;16(1):95.","journal-title":"J Hematol Oncol July"},{"key":"1460_CR23","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.ejca.2022.03.026","volume":"169","author":"RD Kim","year":"2022","unstructured":"Kim RD, Kovari BP, Martinez M, Xie H, Sahin IH, Mehta R, et al. A phase I\/Ib study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer. Eur J Cancer. 2022;169:93\u2013102.","journal-title":"Eur J Cancer"},{"key":"1460_CR24","unstructured":"Jia-Lei W, Jin LI, Shu-Kui Q, Ying C, Qing-Yuan Z, Tian-Shu L et al. Randomized multicenter phase \u2162 trial of oxaliplatin plus raltitrexed versus oxaliplatin plus fluorouracil and leucovorin for advanced colorectal cancer. Chin Clin Oncol. 2012;1:6\u201311."},{"issue":"6","key":"1460_CR25","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/ajco.13511","volume":"17","author":"M Huang","year":"2021","unstructured":"Huang M, Yang Y, Zhu X, Chen Z, Zhang W, Wang C, et al. A prospective phase II study of raltitrexed combined with S-1 as salvage treatment for patients with refractory metastatic colorectal cancer. Asia Pac J Clin Oncol Dec. 2021;17(6):513\u201321.","journal-title":"Asia Pac J Clin Oncol Dec"},{"issue":"41","key":"1460_CR26","doi-asserted-by":"publisher","first-page":"7183","DOI":"10.3748\/wjg.v19.i41.7183","volume":"7","author":"A Yusup","year":"2013","unstructured":"Yusup A, Wang H-J, Rahmutula A, Sayim P, Zhao Z-L, Zhang G-Q. Clinical features and prognosis in colorectal cancer patients with different ethnicities in Northwest China. World J Gastroenterol November. 2013;7(41):7183\u20138.","journal-title":"World J Gastroenterol November"},{"key":"1460_CR27","doi-asserted-by":"publisher","DOI":"10.1177\/20406223231197311","volume":"14","author":"T Deng","year":"2023","unstructured":"Deng T, Duan J, Bai M, Zhang L, Li H, Liu R, et al. Third-line treatment patterns and clinical outcomes for metastatic colorectal cancer: a retrospective real-world study. Ther Adv Chronic Dis. 2023;14:20406223231197311.","journal-title":"Ther Adv Chronic Dis"},{"key":"1460_CR28","doi-asserted-by":"publisher","first-page":"102123","DOI":"10.1016\/j.eclinm.2023.102123","volume":"62","author":"X Fang","year":"2023","unstructured":"Fang X, Zhu N, Zhong C, Wang L, Li J, Weng S, et al. Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial. EClinicalMedicine August. 2023;62:102123.","journal-title":"EClinicalMedicine August"},{"key":"1460_CR29","doi-asserted-by":"crossref","unstructured":"Ottaiano A, Santorsola M, Perri F, Granata V, Cascella M, Sabbatino F et al. Survival and Toxicities of Metastatic Colorectal Cancer Patients Treated with Regorafenib before TAS-102 or Vice Versa: A Mono-Institutional Real-Practice Study.\u00a0J Clin Med. 2023;12(2). Available at: https:\/\/www.mdpi.com\/2077-0383\/12\/2\/596","DOI":"10.3390\/jcm12020596"},{"issue":"8","key":"1460_CR30","doi-asserted-by":"publisher","first-page":"e2118416","DOI":"10.1001\/jamanetworkopen.2021.18416","volume":"2","author":"C Wang","year":"2021","unstructured":"Wang C, Sandhu J, Ouyang C, Ye J, Lee PP, Fakih M. Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1\/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases. JAMA Netw Open August. 2021;2(8):e2118416.","journal-title":"JAMA Netw Open August"},{"issue":"1","key":"1460_CR31","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s41591-020-1131-x","volume":"27","author":"J Yu","year":"2021","unstructured":"Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27(1):152\u201364.","journal-title":"Nat Med"},{"issue":"1","key":"1460_CR32","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s13046-023-02729-7","volume":"22","author":"Y Wang","year":"2023","unstructured":"Wang Y, Zhong X, He X, Hu Z, Huang H, Chen J, et al. Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches. J Exp Clin Cancer Res July. 2023;22(1):177.","journal-title":"J Exp Clin Cancer Res July"},{"issue":"3","key":"1460_CR33","doi-asserted-by":"publisher","first-page":"e000177","DOI":"10.1136\/esmoopen-2017-000177","volume":"2","author":"E Martinelli","year":"2017","unstructured":"Martinelli E, Sforza V, Cardone C, Capasso A, Nappi A, Martini G, et al. Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment. ESMO Open. 2017;2(3):e000177.","journal-title":"ESMO Open"},{"issue":"8","key":"1460_CR34","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/S1470-2045(19)30272-4","volume":"20","author":"TS Bekaii-Saab","year":"2019","unstructured":"Bekaii-Saab TS, Ou F-S, Ahn DH, Boland PM, Ciombor KK, Heying EN, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070\u201382.","journal-title":"Lancet Oncol"}],"container-title":["Journal of Gastrointestinal Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12029-026-01460-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12029-026-01460-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12029-026-01460-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T13:35:06Z","timestamp":1775828106000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12029-026-01460-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1460"],"URL":"https:\/\/doi.org\/10.1007\/s12029-026-01460-8","relation":{},"ISSN":["1941-6636"],"issn-type":[{"value":"1941-6636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"assertion":[{"value":"24 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (ID: IIT-2023-334). All patients provided informed consent for treatment. Due to the retrospective nature of this study, the Ethics Committee of the First Affiliated Hospital of Nanchang University did not require further consent from the patients for the use of their medical records.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All data in this study have been anonymized, and the publication does not involve any personal privacy concerns. Therefore, individual patient consent for publication was not obtained.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"87"}}