{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:12:15Z","timestamp":1790460735170,"version":"4.1.0"},"reference-count":92,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004337","name":"roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Med Oncol"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.<\/jats:p>","DOI":"10.1177\/17588359211031141","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T02:48:13Z","timestamp":1627613293000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":46,"title":["Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab"],"prefix":"10.1177","volume":"13","author":[{"given":"Chiun","family":"Hsu","sequence":"first","affiliation":[{"name":"Graduate Institute of Oncology, National University College of Medicine, National University Hospital, and National University Cancer Center, Taipei"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9957-3615","authenticated-orcid":false,"given":"Lorenza","family":"Rimassa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"},{"name":"IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Hematology Unit, Rozzano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chuan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neubergstrasse 1, Hannover, 30625, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed O.","family":"Kaseb","sequence":"additional","affiliation":[{"name":"Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"bibr1-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708857"},{"key":"bibr2-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70285-7"},{"key":"bibr3-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0179-x"},{"key":"bibr4-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745"},{"key":"bibr5-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02672"},{"key":"bibr6-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31046-2"},{"key":"bibr7-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30351-6"},{"key":"bibr8-17588359211031141","unstructured":"Center for Drug Evaluation and Research. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA, https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma (2020, accessed 1 June 2021)."},{"key":"bibr9-17588359211031141","volume":"79","author":"Ikeda M","year":"2019","journal-title":"Cancer Res"},{"key":"bibr10-17588359211031141","unstructured":"Astor L. FDA holds off on approval of pembrolizumab\/lenvatinib for frontline unresectable HCC. Targeted Oncology, https:\/\/www.targetedonc.com\/view\/fda-denies-approval-of-pembrolizumab-lenvatinib-for-frontline-unresectable-hcc (2020, accessed 1 June 2021)."},{"key":"bibr11-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15573"},{"key":"bibr12-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2019.07.012"},{"key":"bibr13-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.010"},{"key":"bibr14-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2019.05.004"},{"key":"bibr15-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102017"},{"key":"bibr16-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2011-0465"},{"key":"bibr17-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.15.9947"},{"key":"bibr18-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.1195"},{"key":"bibr19-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-010-0988-x"},{"key":"bibr20-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30207-1"},{"key":"bibr21-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30156-X"},{"key":"bibr22-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz394.029"},{"key":"bibr23-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.01307"},{"key":"bibr24-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1080\/17474124.2020.1807939"},{"key":"bibr25-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30011-5"},{"key":"bibr26-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00886-2"},{"key":"bibr27-17588359211031141","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2019-0097"},{"key":"bibr28-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.02.022"},{"key":"bibr29-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.10.029"},{"key":"bibr30-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz394.030"},{"key":"bibr31-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.3_suppl.267"},{"key":"bibr32-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2484"},{"key":"bibr33-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2571"},{"key":"bibr34-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2020.38.15_suppl.4508"},{"key":"bibr35-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.10.134"},{"key":"bibr36-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02076"},{"key":"bibr37-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11121926"},{"key":"bibr38-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.4564"},{"key":"bibr39-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.08.1124"},{"key":"bibr40-17588359211031141","doi-asserted-by":"crossref","first-page":"e0168918","DOI":"10.1371\/journal.pone.0168918","volume":"12","author":"Yang S-C","year":"2017","journal-title":"PLoS One"},{"key":"bibr41-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1586\/17474124.2016.1122523"},{"key":"bibr42-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i1.446"},{"key":"bibr43-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.03.024"},{"key":"bibr44-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-010-9236-9"},{"key":"bibr45-17588359211031141","doi-asserted-by":"publisher","DOI":"10.5009\/gnl19155"},{"key":"bibr46-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-008-9096-8"},{"key":"bibr47-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28906"},{"key":"bibr48-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14366"},{"key":"bibr49-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230X-10-5"},{"key":"bibr50-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s13017-019-0283-9"},{"key":"bibr51-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018080853"},{"key":"bibr52-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-58994-5"},{"key":"bibr53-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2006.11.039"},{"key":"bibr54-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-020-10024-5"},{"key":"bibr55-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00049"},{"key":"bibr56-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-017-0300-z"},{"key":"bibr57-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.6385"},{"key":"bibr58-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx225"},{"key":"bibr59-17588359211031141","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.0012"},{"key":"bibr60-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.11519"},{"key":"bibr61-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1159\/000494844"},{"key":"bibr62-17588359211031141","unstructured":"OPDIVO (nivolumab) injection, for intravenous use. United States prescribing information (USPI), January 2021."},{"key":"bibr63-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2019.37.4_suppl.327"},{"key":"bibr64-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30937-9"},{"key":"bibr65-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001322"},{"key":"bibr66-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000726"},{"key":"bibr67-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2015.11.016"},{"key":"bibr68-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.12.019"},{"key":"bibr69-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31227"},{"key":"bibr70-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1053\/j.semdp.2019.07.009"},{"key":"bibr71-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2020.100170"},{"key":"bibr72-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez465"},{"key":"bibr73-17588359211031141","volume-title":"Poster 1299 presented at the American Association for the Study of Liver Diseases Virtual Congress","author":"Hsu C","year":"2020"},{"key":"bibr74-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001072"},{"key":"bibr75-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0346-6"},{"key":"bibr76-17588359211031141","first-page":"119","volume":"116","author":"Heinzerling L","year":"2019","journal-title":"Dtsch \u00c4rztebl Int"},{"key":"bibr77-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.61.6706"},{"key":"bibr78-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082132"},{"key":"bibr79-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1159\/000496439"},{"key":"bibr80-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17670-y"},{"key":"bibr81-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.09.025"},{"key":"bibr82-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0749-z"},{"key":"bibr83-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1673621"},{"key":"bibr84-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001435"},{"key":"bibr85-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001657"},{"key":"bibr86-17588359211031141","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S91977"},{"key":"bibr87-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.3301"},{"key":"bibr88-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1159\/000335963"},{"key":"bibr89-17588359211031141","doi-asserted-by":"publisher","DOI":"10.2165\/11590180-000000000-00000"},{"key":"bibr90-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0650-9"},{"key":"bibr91-17588359211031141","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i28.3704"},{"key":"bibr92-17588359211031141","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2019-0659"}],"updated-by":[{"DOI":"10.1177\/17588359211047708","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000}}],"container-title":["Therapeutic Advances in Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359211031141","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17588359211031141","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359211031141","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:26:12Z","timestamp":1777587972000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17588359211031141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":92,"alternative-id":["10.1177\/17588359211031141"],"URL":"https:\/\/doi.org\/10.1177\/17588359211031141","relation":{},"ISSN":["1758-8359","1758-8359"],"issn-type":[{"value":"1758-8359","type":"print"},{"value":"1758-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1]]},"article-number":"17588359211031141"}}