{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:51:50Z","timestamp":1792227110539,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Atezolizumab\u2013bevacizumab is established as first-line therapy for unresectable hepatocellular carcinoma (HCC) based on phase III randomized evidence. Although overall safety outcomes were acceptable in the registration trial, the risk of gastrointestinal (GI) and variceal bleeding remains a clinically relevant concern, particularly in patients with cirrhosis and portal hypertension. Differences between trial-based safety estimates and observational data necessitate a focused evaluation of hemorrhagic risk in this setting. Randomized trial data indicate low rates of high-grade bleeding under protocol-driven endoscopic screening and predefined eligibility criteria. In contrast, real-world cohorts report higher incidences of GI and variceal hemorrhage, especially among patients with prior bleeding, untreated or high-risk varices, reduced hepatic reserve, and extensive portal vein tumor thrombosis. Pooled analyses confirm an increased prevalence of bleeding with atezolizumab\u2013bevacizumab compared with non-antiangiogenic systemic therapies, although event rates vary across studies due to differences in patient selection and bleeding definitions. Severe and fatal hemorrhage occurs in a minority of cases and is concentrated in clinically high-risk subgroups. Bleeding during atezolizumab\u2013bevacizumab therapy is influenced by baseline portal hypertension severity, hepatic functional status, and tumor-related vascular involvement. Trial-derived safety data reflect outcomes under controlled conditions and may underestimate risk in broader populations. Structured baseline assessment, endoscopic evaluation, and risk-adapted portal hypertension management are integral to clinical implementation. Prospective studies incorporating standardized hemorrhage definitions and predefined risk stratification frameworks are required to refine patient selection and optimize safety in routine practice.<\/jats:p>","DOI":"10.3390\/cancers18091432","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:47:28Z","timestamp":1777546048000},"page":"1432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gastrointestinal and Variceal Bleeding Under Atezolizumab\u2013Bevacizumab in Hepatocellular Carcinoma: Evidence from Trials to Real-World Practice"],"prefix":"10.3390","volume":"18","author":[{"given":"Hyo-Jin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Uijeongbu St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9663-132X","authenticated-orcid":false,"given":"Hee Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Bucheon St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1111\/liv.14977","article-title":"Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses\u2026","volume":"41","author":"Allaire","year":"2021","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1894","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":"ref_3","doi-asserted-by":"crossref","first-page":"102017","DOI":"10.1016\/j.ctrv.2020.102017","article-title":"Bevacizumab (Avastin\u00ae) in cancer treatment: A review of 15 years of clinical experience and future outlook","volume":"86","author":"Garcia","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.jhep.2021.12.022","article-title":"Baveno VII\u2014Renewing consensus in portal hypertension","volume":"76","author":"Bosch","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.2147\/OTT.S166151","article-title":"Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: A meta-analysis of 85 randomized controlled trials","volume":"11","author":"Xiao","year":"2018","journal-title":"Onco Targets Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"862","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":"ref_7","first-page":"655","article-title":"Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Hepatocellular Carcinoma with Main Trunk and\/or Contralateral Portal Vein Invasion in IMbrave150","volume":"13","author":"Finn","year":"2024","journal-title":"Liver Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"De Gaetano, V., Pallozzi, M., Cerrito, L., Santopaolo, F., Stella, L., Gasbarrini, A., and Ponziani, F.R. (2024). Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives. Cancers, 16.","DOI":"10.3390\/cancers16071388"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1111\/liv.15458","article-title":"A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC","volume":"42","author":"Larrey","year":"2022","journal-title":"Liver Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1111\/apt.18526","article-title":"Risk of Variceal Bleeding in Patients Receiving Atezolizumab-Bevacizumab Treatment for Hepatocellular Carcinoma","volume":"61","author":"Park","year":"2025","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1159\/000533991","article-title":"Safety and Efficacy of Atezolizumab\/Bevacizumab in Patients with Hepatocellular Carcinoma and Impaired Liver Function: A Systematic Review and Meta-Analysis","volume":"13","author":"Pasta","year":"2024","journal-title":"Liver Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101190","DOI":"10.1016\/j.jhepr.2024.101190","article-title":"Heterogeneity in adverse events related to atezolizumab-bevacizumab for hepatocellular carcinoma reported in real-world studies","volume":"6","author":"Campani","year":"2024","journal-title":"JHEP Rep."},{"key":"ref_13","first-page":"590","article-title":"Risk of Bleeding in Hepatocellular Carcinoma Patients Treated with Atezolizumab\/Bevacizumab: A Systematic Review and Meta-Analysis","volume":"13","author":"Song","year":"2024","journal-title":"Liver Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/hep.27376","article-title":"Liver sinusoidal endothelial cells in hepatic fibrosis","volume":"61","author":"DeLeve","year":"2015","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/HYPERTENSIONAHA.117.10271","article-title":"Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease","volume":"71","author":"Pandey","year":"2018","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100316","DOI":"10.1016\/j.jhepr.2021.100316","article-title":"Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy","volume":"3","author":"Iwakiri","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S121","DOI":"10.1002\/hep.20993","article-title":"The hyperdynamic circulation of chronic liver diseases: From the patient to the molecule","volume":"43","author":"Iwakiri","year":"2006","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/sj.bjc.6603813","article-title":"Mechanisms of adverse effects of anti-VEGF therapy for cancer","volume":"96","author":"Kamba","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1111\/jth.15354","article-title":"Thrombotic and bleeding risk of angiogenesis inhibitors in patients with and without malignancy","volume":"19","author":"Watson","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1042\/CS20200300","article-title":"Cardiovascular toxicity of angiogenesis inhibitors and immune checkpoint inhibitors: Synergistic anti-tumour effects at the cost of increased cardiovascular risk?","volume":"135","author":"Manintveld","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e260066","DOI":"10.1136\/bcr-2024-260066","article-title":"Hepatic sinusoidal obstruction syndrome after immune-checkpoint-inhibitor therapy: When the liver sends SOS","volume":"17","author":"Kasper","year":"2024","journal-title":"BMJ Case Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1016\/j.apsb.2021.10.003","article-title":"Mechanisms of immune checkpoint inhibitor-mediated liver injury","volume":"11","author":"Shojaie","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000528272","article-title":"IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study","volume":"12","author":"Kudo","year":"2023","journal-title":"Liver Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102179","DOI":"10.1016\/j.eclinm.2023.102179","article-title":"Effectiveness and safety of atezolizumab-bevacizumab in patients with unresectable hepatocellular carcinoma: A systematic review and meta-analysis","volume":"63","author":"Kulkarni","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101431","DOI":"10.1016\/j.jhepr.2025.101431","article-title":"Efficacy of atezolizumab plus bevacizumab for unresectable HCC: Systematic review and meta-analysis of real-world evidence","volume":"7","author":"Manfredi","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tran, N.H., Soefje, S.A., Rangarajan, N., Krishnappa, P., Wagner, T.E., Valerio, S.J., Anderson, R., and Olson, J.C. (2025). Patient Characteristics, Treatment Patterns, and Outcomes in Unresectable Hepatocellular Carcinoma Treated with First-Line Systemic Therapy in the United States. Cancers, 17.","DOI":"10.3390\/cancers17213499"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"315","DOI":"10.5009\/gnl250133","article-title":"Prognostic Impact of Varices and Hemorrhagic Events in Hepatocellular Carcinoma Patients Treated with Atezolizumab Plus Bevacizumab","volume":"20","author":"Park","year":"2025","journal-title":"Gut Liver"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1159\/000531744","article-title":"Balancing Efficacy and Tolerability of First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis","volume":"13","author":"Celsa","year":"2024","journal-title":"Liver Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ejca.2022.06.058","article-title":"Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials","volume":"174","author":"Fulgenzi","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.jhep.2022.11.019","article-title":"Treatment of portal hypertension in patients with HCC in the era of Baveno VII","volume":"78","author":"Thabut","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1002\/cncr.25573","article-title":"Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement","volume":"117","author":"Erinjeri","year":"2011","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1097\/SAP.0b013e3181828141","article-title":"A review on bevacizumab and surgical wound healing: An important warning to all surgeons","volume":"62","author":"Gordon","year":"2009","journal-title":"Ann. Plast. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1470-2045(09)70341-9","article-title":"Vascular endothelial growth factor targeted therapy in the perioperative setting: Implications for patient care","volume":"11","author":"Bose","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1097\/CAD.0b013e328349c7bb","article-title":"Wound healing and catheter thrombosis after implantable venous access device placement in 266 breast cancers treated with bevacizumab therapy","volume":"22","author":"Kriegel","year":"2011","journal-title":"Anticancer. Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.dld.2019.06.019","article-title":"Ulcer bleeding after band ligation of esophageal varices: Risk factors and prognosis","volume":"52","author":"Cachero","year":"2020","journal-title":"Dig. Liver Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jhep.2022.02.004","article-title":"Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma","volume":"77","author":"Allaire","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17588359211031141","DOI":"10.1177\/17588359211031141","article-title":"Immunotherapy in hepatocellular carcinoma: Evaluation and management of adverse events associated with atezolizumab plus bevacizumab","volume":"13","author":"Hsu","year":"2021","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_38","first-page":"EVIDoa2100070","article-title":"Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma","volume":"1","author":"Lau","year":"2022","journal-title":"NEJM Evid."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1432\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:59:02Z","timestamp":1777546742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/9\/1432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18091432"],"URL":"https:\/\/doi.org\/10.3390\/cancers18091432","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}