Risk of Bleeding in Hepatocellular Carcinoma Patients Treated with Atezolizumab/Bevacizumab: A Systematic Review and Meta-Analysis

Overview

Journal Liver Cancer

Date 2024 Dec 17

PMID 39687040

Authors

Young-Gi Song

Kyeong-Min Yeom

Eun Ae Jung

Sang Gyune Kim

Young Seok Kim

Jeong-Ju Yoo

Affiliations

Soon will be listed here.

Abstract

Introduction: The combination of atezolizumab/bevacizumab has emerged as an effective first-line treatment for advanced hepatocellular carcinoma (HCC). However, this therapy is potentially associated with bleeding complications, warranting a comprehensive analysis of their incidence and severity. This meta-analysis aims to synthesize available evidence from clinical trials and observational studies to quantify the prevalence of bleeding following atezolizumab/bevacizumab administration.

Methods: This meta-analysis focused on HCC treatment using atezolizumab/bevacizumab, particularly examining bleeding complications. It determined the prevalence of bleeding post-administration and compared the risk ratio with tyrosine kinase inhibitors (sorafenib or lenvatinib). Risk factors for bleeding complications were also evaluated.

Results: From 28 studies involving 3,895 patients, the pooled prevalence of bleeding side effects was 8.42% (95% CI: 5.72-11.54). Grade III or IV bleeding occurred in 4.42% (95% CI: 2.64-6.10) of patients, with grade V bleeding observed in 2.06% (95% CI: 0.56-4.22). Gastrointestinal bleeding, predominantly variceal, was the most common, with a prevalence of 5.48% (95% CI: 3.98-7.17). Subgroup analysis indicated variability in bleeding rates based on study design and geographical location. Atezolizumab/bevacizumab treatment exhibited a 2.11 times higher prevalence of bleeding compared to tyrosine kinase inhibitors (95% CI: 1.21-3.66). Meta-regression identified high body mass index (BMI) and higher proportion of albumin-bilirubin (ALBI) grade 3 as significant risk factors for bleeding complications.

Conclusion: Atezolizumab/bevacizumab therapy for advanced HCC carries a heightened risk of gastrointestinal bleeding, exceeding that of tyrosine kinase inhibitors. High BMI and higher ALBI grade are key predictors of bleeding complications, emphasizing the need for cautious patient selection and monitoring.

References

Qin S, Ren Z, Feng Y, Yau T, Wang B, Zhao H . Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Liver Cancer. 2021; 10(4):296-308. PMC: 8339481. DOI: 10.1159/000513486. View

Yeom K, Song Y, Yoo J, Kim S, Kim Y . Reduced-Dose or Discontinuation of Bevacizumab Might Be Considered after Variceal Bleeding in Patients with Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab: Case Reports. Medicina (Kaunas). 2024; 60(1). PMC: 10820589. DOI: 10.3390/medicina60010157. View

Cheng A, Qin S, Ikeda M, Galle P, Ducreux M, Kim T . Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2021; 76(4):862-873. DOI: 10.1016/j.jhep.2021.11.030. View

Chaibi S, Larrey E, Couty J, Sultanik P, Campani C, Blaise L . Albumin infusion reduces ascite occurrence in Child-Pugh B patients treated by Atezolizumab-Bevacizumab for advanced HCC. Clin Res Hepatol Gastroenterol. 2023; 47(8):102199. DOI: 10.1016/j.clinre.2023.102199. View

Lee S, Kwon J, Lee S, Lee H, Kim H, Kim C . A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis. Cancers (Basel). 2023; 15(17). PMC: 10486735. DOI: 10.3390/cancers15174423. View

Kole C, Charalampakis N, Tsakatikas S, Vailas M, Moris D, Gkotsis E . Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers (Basel). 2020; 12(10). PMC: 7600093. DOI: 10.3390/cancers12102859. View

Ollivier-Hourmand I, Allaire M, Cervoni J . Management of portal hypertension in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma. J Hepatol. 2022; 77(2):566-567. DOI: 10.1016/j.jhep.2022.02.004. View

Cheon J, Kim H, Kim H, Kim C, Kim I, Kang B . Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2023; 15:17588359221148541. PMC: 10495918. DOI: 10.1177/17588359221148541. View

Cheon J, Yoo C, Hong J, Kim H, Lee D, Lee M . Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Liver Int. 2021; 42(3):674-681. DOI: 10.1111/liv.15102. View

10.

DAlessio A, Fulgenzi C, Nishida N, Schonlein M, von Felden J, Schulze K . Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. Hepatology. 2022; 76(4):1000-1012. PMC: 9790703. DOI: 10.1002/hep.32468. View

11.

Hayakawa Y, Tsuchiya K, Kurosaki M, Yasui Y, Kaneko S, Tanaka Y . Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice. Invest New Drugs. 2021; 40(2):392-402. DOI: 10.1007/s10637-021-01185-4. View

12.

Su C, Teng W, Lin P, Jeng W, Chen K, Hsieh Y . Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Cancer Med. 2022; 12(6):7077-7089. PMC: 10067067. DOI: 10.1002/cam4.5506. View

13.

Song Y, Yoo J, Kim S, Kim Y . Complications of immunotherapy in advanced hepatocellular carcinoma. J Liver Cancer. 2023; 24(1):9-16. PMC: 10990673. DOI: 10.17998/jlc.2023.11.21. View

14.

Cao F, Shi C, Zhang G, Luo J, Zheng J, Hao W . Improved clinical outcomes in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus atezolizumab and bevacizumab: a bicentric retrospective study. BMC Cancer. 2023; 23(1):873. PMC: 10506240. DOI: 10.1186/s12885-023-11389-x. View

15.

Charonpongsuntorn C, Tanasanvimon S, Korphaisarn K, Payapwattanawong S, Siripoon T, Pakvisal N . Efficacy, Safety, and Patient-Reported Outcomes of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Thailand: A Multicenter Prospective Study. JCO Glob Oncol. 2022; 8:e2200205. PMC: 10166432. DOI: 10.1200/GO.22.00205. View

16.

Kulkarni A, Krishna V, Kumar K, Sharma M, Patodiya B, Khan A . Safety and Efficacy of Atezolizumab-Bevacizumab in Real World: The First Indian Experience. J Clin Exp Hepatol. 2023; 13(4):618-623. PMC: 10333935. DOI: 10.1016/j.jceh.2023.02.003. View

17.

Brahmer J, Lacchetti C, Schneider B, Atkins M, Brassil K, Caterino J . Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018; 36(17):1714-1768. PMC: 6481621. DOI: 10.1200/JCO.2017.77.6385. View

18.

Finn R, Qin S, Ikeda M, Galle P, Ducreux M, Kim T . Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020; 382(20):1894-1905. DOI: 10.1056/NEJMoa1915745. View

19.

Kim B, Cheon J, Kim H, Kang B, Ha Y, Kim D . Atezolizumab/Bevacizumab vs. Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Real-World, Multi-Center Study. Cancers (Basel). 2022; 14(7). PMC: 8996911. DOI: 10.3390/cancers14071747. View

20.

Tada F, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J . Efficacy and safety of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma patients with esophageal-gastric varices. J Gastroenterol. 2023; 58(11):1134-1143. DOI: 10.1007/s00535-023-02026-2. View