Subscribe to RSS
DOI: 10.1055/s-0044-1779713
Hepatocellular Carcinoma: Advances in Systemic Therapy
Abstract
Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing over 90% of cases globally and ranking as the third leading cause of cancer-related death. This article reviews the evolving landscape of systemic therapies for advanced HCC, emphasizing recent advancements and their impact on patient outcomes. The advent of molecular targeted therapies has transformed HCC management, with sorafenib being the first FDA-approved molecular targeted therapy, setting a standard for a decade. However, recent breakthroughs involve the combination of atezolizumab and bevacizumab, demonstrating superior outcomes over sorafenib, leading to FDA approval in 2020. Another notable combination is tremelimumab and durvalumab, showing efficacy in a multinational phase III trial. Beyond these combinations, this article explores the role of other first-line treatments and subsequent therapies after progression. The evolving landscape of systemic therapies for HCC reflects a paradigm shift, with immunotherapy combinations emerging as key players alongside targeted therapies. This article highlights the complexity of treatment decisions, considering individual patient characteristics and disease etiology, and underscores the ongoing quest to optimize both systemic and local–regional therapies for improved long-term outcomes in HCC patients.
Publication History
Article published online:
14 March 2024
© 2024. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022; 72 (01) 7-33
- 2 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16 (10) 589-604
- 3 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
- 4 Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet 2022; 400 (10360): 1345-1362
- 5 Yen YH, Cheng YF, Wang JH, Lin CC, Wang CC. Characteristics and etiologies of hepatocellular carcinoma in patients without cirrhosis: when east meets west. PLoS One 2021; 16 (01) e0244939
- 6 Karaoğullarından Ü, Üsküdar O, Odabaş E, Ak N, Kuran S. Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers: clinicomorphologic findings and prognostic factors. Turk J Gastroenterol 2023; 34 (03) 262-269
- 7 Gordan JD, Kennedy EB, Abou-Alfa GK. et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO Guideline. J Clin Oncol 2020; 38 (36) 4317-4345
- 8 Yang C, Zhang H, Zhang L. et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2023; 20 (04) 203-222
- 9 Beaufrère A, Calderaro J, Paradis V. Combined hepatocellular-cholangiocarcinoma: An update. J Hepatol 2021; 74 (05) 1212-1224
- 10 Coffin P, He A. Hepatocellular carcinoma: past and present challenges and progress in molecular classification and precision oncology. Int J Mol Sci 2023; 24 (17) 13274
- 11 Girardi DM, Sousa LP, Miranda TA, Haum FNC, Pereira GCB, Pereira AAL. Systemic therapy for advanced hepatocellular carcinoma: current stand and perspectives. Cancers (Basel) 2023; 15 (06) 1680
- 12 Llovet JM, Di Bisceglie AM, Bruix J. et al; Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100 (10) 698-711
- 13 Lee YR. A multidisciplinary approach with immunotherapies for advanced hepatocellular carcinoma. J Liver Cancer 2023; 23 (02) 316-329
- 14 Coffman-D'Annibale K, Xie C, Hrones DM, Ghabra S, Greten TF, Monge C. The current landscape of therapies for hepatocellular carcinoma. Carcinogenesis 2023; 44 (07) 537-548
- 15 Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391 (10127): 1301-1314
- 16 Ghaziani TT, Dhanasekaran R. Recent progress in systemic therapy for hepatocellular cancer (HCC). Curr Treat Options Gastroenterol 2021; 19 (02) 351-368
- 17 Totoki Y, Tatsuno K, Covington KR. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet 2014; 46 (12) 1267-1273
- 18 Wu TC, Shen YC, Cheng AL. Evolution of systemic treatment for advanced hepatocellular carcinoma. Kaohsiung J Med Sci 2021; 37 (08) 643-653
- 19 Marisi G, Cucchetti A, Ulivi P. et al. Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?. World J Gastroenterol 2018; 24 (36) 4152-4163
- 20 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
- 21 Cheng AL, Qin S, Ikeda M. et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022; 76 (04) 862-873
- 22 Rimini M, Persano M, Tada T. et al. Real-world data for atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: How does adherence to the IMbrave150 trial inclusion criteria impact prognosis?. Target Oncol 2023; 18 (02) 221-233
- 23 Cheon J, Kim H, Kim HS. et al. Atezolizumab plus bevacizumab in patients with Child-Pugh B advanced hepatocellular carcinoma. Ther Adv Med Oncol 2023; 15: 17 588359221148541
- 24 Abou-Alfa GK, Lau G, Kudo M. et al. Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer). Future Oncol 2023; 19 (38) 2505-2516
- 25 Bruix J, Raoul JL, Sherman M. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012; 57 (04) 821-829
- 26 Cheng AL, Kang YK, Chen Z. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10 (01) 25-34
- 27 Kelley RK, Ryoo BY, Merle P. et al. Second-line cabozantinib after sorafenib treatment for advanced hepatocellular carcinoma: a subgroup analysis of the phase 3 CELESTIAL trial. ESMO Open 2020; 5 (04) e000714
- 28 Ciliberto D, Caridà G, Staropoli N. et al. First-line systemic treatment for hepatocellular carcinoma: a systematic review and network meta-analysis. Heliyon 2023; 9 (08) e18696
- 29 Tang W, Chen Z, Zhang W. et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5 (01) 87
- 30 Yamashita T, Kudo M, Ikeda K. et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol 2020; 55 (01) 113-122
- 31 Kudo M, Finn RS, Edeline J. et al; KEYNOTE-224 Investigators. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer 2022; 167: 1-12
- 32 Kobayashi K, Ogasawara S, Maruta S. et al. A prospective study exploring the safety and efficacy of lenvatinib for patients with advanced hepatocellular carcinoma and high tumor burden: the LAUNCH study. Clin Cancer Res 2023; 29 (23) 4760-4769
- 33 Chan LL, Chan SL. The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment. Clin Mol Hepatol 2023; 29 (04) 909-923
- 34 Bruix J, Qin S, Merle P. et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389 (10064): 56-66
- 35 Zhu AX, Kang YK, Yen CJ. et al; REACH-2 Study Investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20 (02) 282-296
- 36 Yau T, Kang YK, Kim TY. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020; 6 (11) e204564
- 37 Yau T, Park JW, Finn RS. et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2022; 23 (01) 77-90
- 38 Schenker M, Burotto M, Richardet M. et al. Abstract CT022: CheckMate 848: a randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Cancer Res 2022; 82 (12) CT022
- 39 Finn RS, Ryoo BY, Merle P. et al; KEYNOTE-240 Investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020; 38 (03) 193-202
- 40 Fu Y, Zeng CH, An C, Liu Y, Shin JH, Li X. How biology guides the combination of locoregional interventional therapies and immunotherapy for hepatocellular carcinoma: cytokines and their roles. Cancers (Basel) 2023; 15 (04) 1324
- 41 Li X, Wang Y, Ye X, Liang P. Locoregional combined with systemic therapies for advanced hepatocellular carcinoma: an inevitable trend of rapid development. Front Mol Biosci 2021; 8: 635243
- 42 den Brok MH, Sutmuller RP, Nierkens S. et al. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res 2006; 66 (14) 7285-7292
- 43 Duffy AG, Ulahannan SV, Makorova-Rusher O. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66 (03) 545-551
- 44 Shuanggang C, Shen L, Qiu Z. et al. Transarterial chemoembolization combined with microwave ablation and apatinib in patients with Barcelona Clinic Liver Cancer Stage C hepatocellular carcinoma: a propensity score matching analysis. J Cancer Res Ther 2020; 16 (02) 250-257
- 45 Ricke J, Klümpen HJ, Amthauer H. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71 (06) 1164-1174
- 46 Di Federico A, Rizzo A, Carloni R. et al. Atezolizumab-bevacizumab plus Y-90 TARE for the treatment of hepatocellular carcinoma: preclinical rationale and ongoing clinical trials. Expert Opin Investig Drugs 2022; 31 (04) 361-369