{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:53:06Z","timestamp":1789498386270,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and aims<\/jats:title><jats:p>The efficacy and safety of systemic atezolizumab and bevacizumab (atezo\/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo\/bev in treatment of these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo\/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3\/4 TRAE was hypertension (16.7%). There was no treatment-related deaths.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>IMRT combined with atezo\/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:uri>http:\/\/www.chictr.org.cn<\/jats:uri>, Identifier ChiCTR2200061793.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1107542","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T12:07:13Z","timestamp":1676549233000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study"],"prefix":"10.3389","volume":"14","author":[{"given":"Kang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Jun","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Ming","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Qiang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong-Han","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Ya","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Zhi","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Fei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Wei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Kun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Yee","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Qun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","author":"Asrani","year":"2019","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ijsu.2015.05.009","article-title":"The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus","volume":"20","author":"Zhang","year":"2015","journal-title":"Int J Surg"},{"key":"B3","doi-asserted-by":"publisher","first-page":"696","DOI":"10.5009\/gnl.2013.7.6.696","article-title":"Practical effect of sorafenib monotherapy on advanced hepatocellular carcinoma and portal vein tumor thrombosis","volume":"7","author":"Jeong","year":"2013","journal-title":"Gut Liver"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.5114\/pg.2015.52470","article-title":"Sorafenib for the treatment of hepatocellular carcinoma with portal vein tumour thrombosis: A systematic review of comparative studies","volume":"10","author":"Qi","year":"2015","journal-title":"Prz Gastroenterol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230X-14-84","article-title":"Overall survival in response to sorafenib versus radiotherapy in unresectable hepatocellular carcinoma with major portal vein tumor thrombosis: Propensity score analysis","volume":"14","author":"Nakazawa","year":"2014","journal-title":"BMC Gastroenterol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/S1470-2045(21)00151-0","article-title":"Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): An open-label, randomised, phase 3 trial","volume":"22","author":"Galle","year":"2021","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.030","article-title":"Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma","volume":"76","author":"Cheng","year":"2022","journal-title":"J Hepatol"},{"key":"B10","first-page":"A 259","article-title":"IMbrave150: Updated efficacy and safety by risk status in patients (pts) receiving atezolizumab (atezo)+ bevacizumab (bev) vs sorafenib (sor) as first-line treatment for unresectable hepatocellular carcinoma (HCC)","volume":"59","author":"Galle","year":"2021","journal-title":"Z f\u00fcr Gastroenterologie"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.4073","article-title":"IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and\/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global ph III study","volume":"39","author":"Breder","year":"2021","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.211545","article-title":"Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib for hepatocellular carcinoma with major portal vein tumor thrombosis: A randomized trial","volume":"303","author":"Zheng","year":"2022","journal-title":"Radiology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0250","article-title":"Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: A randomized clinical trial","volume":"5","author":"He","year":"2019","journal-title":"JAMA Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-021-10173-y","article-title":"Stereotactic body radiotherapy versus intensity-modulated radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis","volume":"15","author":"Li","year":"2021","journal-title":"Hepatol Int"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/9943683","article-title":"Combination intensity-modulated radiotherapy and sorafenib improves outcomes in hepatocellular carcinoma with portal vein tumor thrombosis","volume":"2021","author":"Abulimiti","year":"2021","journal-title":"J Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02184","article-title":"Neoadjuvant three-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: A randomized, open-label, multicenter controlled study","volume":"37","author":"Wei","year":"2019","journal-title":"J Clin Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1177\/1533033821995286","article-title":"Evaluation of the efficacy and toxicity of radiotherapy for type III-IV portal vein tumor thrombi","volume":"20","author":"Bai","year":"2021","journal-title":"Technol Cancer Res Treat"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14081901","article-title":"Outcomes and toxicities of modern combined modality therapy with atezolizumab plus bevacizumab and radiation therapy for hepatocellular carcinoma","volume":"14","author":"Manzar","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"Electronic address eee, European association for the study of the l. EASL clinical practice guidelines: Management of hepatocellular carcinoma","volume":"69","year":"2018","journal-title":"J Hepatol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1159\/000503685","article-title":"Chinese Expert consensus on multidisciplinary diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus (2018 edition)","volume":"9","author":"Cheng","year":"2020","journal-title":"Liver Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/s1055-3207(02)00082-0","article-title":"Results of hepatic resection for hepatocellular carcinoma invading major portal and\/or hepatic veins","volume":"12","author":"Ikai","year":"2003","journal-title":"Surg Oncol Clin N Am"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.21037\/hbsn-19-810","article-title":"A new staging system for hepatocellular carcinoma associated with portal vein tumor thrombus","volume":"10","author":"Lau","year":"2021","journal-title":"Hepatobiliary Surg Nutr"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(19)30178-5","article-title":"Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: Comparing east and west","volume":"4","author":"Lu","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29086","article-title":"AASLD guidelines for the treatment of hepatocellular carcinoma","volume":"67","author":"Heimbach","year":"2018","journal-title":"Hepatology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2019.0019","article-title":"Guidelines insights: Hepatobiliary cancers, version 2.2019","volume":"17","author":"Benson","year":"2019","journal-title":"J Natl Compr Canc Netw"},{"key":"B26","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1159\/000509424","article-title":"Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition)","volume":"9","author":"Zhou","year":"2020","journal-title":"Liver Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2011.03.019","article-title":"Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: Long-term patient outcomes","volume":"82","author":"Yoon","year":"2012","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.addr.2017.01.004","article-title":"Radiotherapy for cancer: Present and future","volume":"109","author":"Allen","year":"2017","journal-title":"Adv Drug Delivery Rev"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1608986","article-title":"Recent developments in radiotherapy","volume":"377","author":"Citrin","year":"2017","journal-title":"N Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133212","article-title":"Tumor microenvironment as a \u201cGame changer\u201d in cancer radiotherapy","volume":"20","author":"Jarosz-Biej","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.5847","article-title":"Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: A randomized clinical trial","volume":"4","author":"Yoon","year":"2018","journal-title":"JAMA Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13030457","article-title":"Radiotherapy-immunotherapy combination: How will we bridge the gap between pre-clinical promise and effective clinical delivery","volume":"13","author":"Romano","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15102","article-title":"Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma","volume":"42","author":"Cheon","year":"2022","journal-title":"Liver Int"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2022.07.035","article-title":"Risk of variceal bleeding in patients with advanced hepatocellular carcinoma receiving Atezolizumab\/Bevacizumab","author":"Ha","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/srep42577","article-title":"The impact of esophagogastric varices on the prognosis of patients with hepatocellular carcinoma","volume":"7","author":"Hsieh","year":"2017","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-011-1551-4","article-title":"Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages","volume":"18","author":"D\u2019Avola","year":"2011","journal-title":"Ann Surg Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02091","article-title":"Efficacy and safety of sintilimab plus anlotinib for PD-L1-Positive recurrent or metastatic cervical cancer: A multicenter, single-arm, prospective phase II trial","volume":"40","author":"Xu","year":"2022","journal-title":"J Clin Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.04.005","article-title":"Evaluation of TMB as a predictive biomarker in patients with solid cancers treated with anti-PD-1\/CTLA-4 combination immunotherapy","volume":"39","author":"Klein","year":"2021","journal-title":"Cancer Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-2052","article-title":"Prostaglandin E1 inhibits GLI2 amplification-associated activation of the hedgehog pathway and drug refractory tumor growth","volume":"80","author":"Wu","year":"2020","journal-title":"Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.348","article-title":"Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells","volume":"36","author":"Faiao-Flores","year":"2017","journal-title":"Oncogene"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1107542\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T12:07:17Z","timestamp":1676549237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1107542\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2023.1107542"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1107542","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]},"article-number":"1107542"}}