Advertisement

Dual immune checkpoint inhibitors or combined with anti-VEGF agents in advanced, unresectable hepatocellular carcinoma

  • Author Footnotes
    1 These authors contributed equally to this study.
    Bo Zhang
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Baorui Tao
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
    Yitong Li
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Chenhe Yi
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Zhifei Lin
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Yue Ma
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Jiahao Han
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Weiqing Shao
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Zhenmei Chen
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Jing Lin
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Jinhong Chen
    Correspondence
    Correspondence author at: Department of General Surgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, PR China.
    Affiliations
    Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    Cancer Metastasis Institute, Fudan University, Shanghai 200040, PR China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this study.
Published:December 31, 2022DOI:https://doi.org/10.1016/j.ejim.2022.12.025

      Highlights

      • Immune checkpoint inhibitor-based combination immunotherapy demonstrated superior clinical benefit with tolerable toxicity in advanced hepatocellular carcinoma.
      • Combination immunotherapy resulted in a significantly better overall survival and progression-free survival outcomes than sorafenib.
      • PD-1/L1 inhibitors plus anti-VEGF agents showed superiority of survival benefit than PD-1/L1 inhibitors plus CTLA-4 inhibitors.

      Abstract

      Background

      Immune checkpoint inhibitor monotherapy did not show superiority of survival over standard therapy in advanced hepatocellular carcinoma. The combination immunotherapy including dual immune checkpoint inhibitors or combined with anti-VEGF agents have become a trend, but not fully evaluated. This study aimed to evaluate and compare distinct combination immunotherapy on efficacy in advanced hepatocellular carcinoma.

      Methods

      PubMed, Embase, Web of Science and Cochrane databases were systematically searched from inception to January 31, 2022. The primary endpoints were overall objective response rate (ORR), disease control rate (DCR), six-month progression-free survival rate (PFSR6m) and one-year overall survival rate (OSR1y).

      Results

      11 studies with 16 independent cohorts and 3342 patients were included in the meta-analysis. Compared with first-line sorafenib, combination immunotherapy resulted in a significant improvement in ORR (RR, 2.74; 95%CI, 1.55–4.85; p = 0.0006), PFS (HR, 0.57; 95%CI, 0.49–0.65; p<0.0001) and OS (HR, 0.65; 95%CI, 0.52–0.82; p = 0.0002). Based on RECIST 1.1, the pooled ORR, PFSR6m and OSR1y for combination immunotherapy were 24.6% (95%CI: 20.3%-29.6%), 42.0% (95%CI: 34.2%-50.3%) and 61.8% (95%CI: 57.7%-65.7%), respectively. In distinct combination regimens, PD-1/L1 inhibitors plus anti-VEGF agents showed a significant superiority of clinical benefit than PD-1/L1 inhibitors plus CTLA-4 inhibitors (ORR: 25.2% vs 23.4%, p = 0.033; PFSR6m: 47.4% vs 23.2%, p<0.001; OSR1y: 65.1% vs 55.0%, p = 0.001).

      Conclusions

      This study was the first meta-analysis to demonstrate the better survival benefit and tolerable toxicity of combination immunotherapy than standard therapy in advanced hepatocellular carcinoma. Compared with PD-1/L1 inhibitors plus CTLA-4 inhibitors, the regimens of PD-1/L1 inhibitors plus anti-VEGF agents may be associated with a significantly better clinical benefit. The difference in long-term survival and response population between two distinct combination regimens required further exploration.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Villanueva A.
        Hepatocellular carcinoma.
        N Engl J Med. 2019; 380: 1450-1462
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics.
        CA Cancer J Clin. 2020; 70 (2020): 7-30
        • Zeng H.
        • Chen W.
        • Zheng R.
        • Zhang S.
        • Ji J.S.
        • Zou X.
        • Xia C.
        • Sun K.
        • Yang Z.
        • Li H.
        • et al.
        Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries.
        Lancet Glob Health. 2018; 6: e555-e567
        • Cheng A.L.
        • Kang Y.K.
        • Chen Z.
        • Tsao C.J.
        • Qin S.
        • Kim J.S.
        • Luo R.
        • Feng J.
        • Ye S.
        • Yang T.S.
        • 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: 25-34
        • Kudo M.
        • Finn R.S.
        • Qin S.
        • Han K.H.
        • Ikeda K.
        • Piscaglia F.
        • Baron A.
        • Park J.W.
        • Han G.
        • Jassem J.
        • et al.
        Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
        Lancet. 2018; 391: 1163-1173
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • de Oliveira A.C.
        • Santoro A.
        • Raoul J.L.
        • Forner A.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • Vogel A.
        • Cervantes A.
        • Chau I.
        • Daniele B.
        • Llovet J.M.
        • Meyer T.
        • Nault J.C.
        • Neumann U.
        • Ricke J.
        • Sangro B.
        • et al.
        Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2018; 29 (iv238-iv255)
        • El-Khoueiry A.B.
        • Sangro B.
        • Yau T.
        • Crocenzi T.S.
        • Kudo M.
        • Hsu C.
        • Kim T.Y.
        • Choo S.P.
        • Trojan J.
        • Welling T.H.R.
        • et al.
        Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
        Lancet. 2017; 389: 2492-2502
        • Zhu A.X.
        • Finn R.S.
        • Edeline J.
        • Cattan S.
        • Ogasawara S.
        • Palmer D.
        • Verslype C.
        • Zagonel V.
        • Fartoux L.
        • Vogel A.
        • et al.
        Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
        Lancet Oncol. 2018; 19: 940-952
        • Finn R.S.
        • Ryoo B.Y.
        • Merle P.
        • Kudo M.
        • Bouattour M.
        • Lim H.Y.
        • Breder V.
        • Edeline J.
        • Chao Y.
        • Ogasawara S.
        • et al.
        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: 193-202
        • Yau T.
        • Park J.W.
        • Finn R.S.
        • Cheng A.L.
        • Mathurin P.
        • Edeline J.
        • Kudo M.
        • Harding J.J.
        • Merle P.
        • Rosmorduc O.
        • et al.
        Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.
        Lancet Oncol. 2022; 23: 77-90
        • Chen D.S.
        • Hurwitz H.
        Combinations of Bevacizumab with cancer immunotherapy.
        Cancer J. 2018; 24: 193-204
        • Morse M.A.
        • Sun W.
        • Kim R.
        • He A.R.
        • Abada P.B.
        • Mynderse M.
        • Finn R.S.
        The role of angiogenesis in hepatocellular carcinoma.
        Clin Cancer Res. 2019; 25: 912-920
        • Hegde P.S.
        • Wallin J.J.
        • Mancao C.
        Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
        Semin Cancer Biol. 2018; 52: 117-124
        • Motz G.T.
        • Santoro S.P.
        • Wang L.P.
        • Garrabrant T.
        • Lastra R.R.
        • Hagemann I.S.
        • Lal P.
        • Feldman M.D.
        • Benencia F.
        • Coukos G.
        Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors.
        Nat Med. 2014; 20: 607-615
        • Roland C.L.
        • Dineen S.P.
        • Lynn K.D.
        • Sullivan L.A.
        • Dellinger M.T.
        • Sadegh L.
        • Sullivan J.P.
        • Shames D.S.
        • Brekken R.A.
        Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts.
        Mol Cancer Ther. 2009; 8: 1761-1771
        • Voron T.
        • Colussi O.
        • Marcheteau E.
        • Pernot S.
        • Nizard M.
        • Pointet A.L.
        • Latreche S.
        • Bergaya S.
        • Benhamouda N.
        • Tanchot C.
        • et al.
        VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
        J Exp Med. 2015; 212: 139-148
        • Wallin J.J.
        • Bendell J.C.
        • Funke R.
        • Sznol M.
        • Korski K.
        • Jones S.
        • Hernandez G.
        • Mier J.
        • He X.
        • Hodi F.S.
        • et al.
        Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
        Nat Commun. 2016; 7: 12624
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • Galle P.R.
        • Ducreux M.
        • Kim T.Y.
        • Kudo M.
        • Breder V.
        • Merle P.
        • Kaseb A.O.
        • et al.
        Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
        N Engl J Med. 2020; 382: 1894-1905
        • Buchbinder E.I.
        • Desai A.
        CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition.
        Am J Clin Oncol. 2016; 39: 98-106
        • Abou-Alfa G.K.
        • Chan S.L.
        • Kudo M.
        • Lau G.
        • Kelley R.K.
        • Furuse J.
        • Sukeepaisarnjaroen W.
        • Kang Y.-K.
        • Dao T.V.
        • Toni E.N.D.
        • et al.
        Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC).
        HIMALAYA. 2022; 40 (379-379)
        • Da L.
        • Teng Y.
        • Wang N.
        • Zaguirre K.
        • Liu Y.
        • Qi Y.
        • Song F.
        Organ-specific immune-related adverse events associated with immune checkpoint inhibitor monotherapy versus combination therapy in cancer: a meta-analysis of randomized controlled trials.
        Front Pharmacol. 2019; 10: 1671
        • Park R.
        • Lopes L.
        • Cristancho C.R.
        • Riano I.M.
        • Saeed A.
        Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis.
        Front Oncol. 2020; 10: 258
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • Group P.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche P.C.
        • Juni P.
        • Moher D.
        • Oxman A.D.
        • Savovic J.
        • Schulz K.F.
        • Weeks L.
        • Sterne J.A.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Bang Y.J.
        • Golan T.
        • Dahan L.
        • Fu S.
        • Moreno V.
        • Park K.
        • Geva R.
        • De Braud F.
        • Wainberg Z.A.
        • Reck M.
        • et al.
        Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: an open-label, phase Ia/b study (JVDJ).
        Eur J Cancer. 2020; 137: 272-284
        • Kelley R.K.
        • Sangro B.
        • Harris W.
        • Ikeda M.
        • Okusaka T.
        • Kang Y.K.
        • Qin S.
        • Tai D.W.
        • Lim H.Y.
        • Yau T.
        • et al.
        Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study.
        J Clin Oncol. 2021; 39: 2991-3001
        • Kudo M.
        • Motomura K.
        • Wada Y.
        • Inaba Y.
        • Sakamoto Y.
        • Kurosaki M.
        • Umeyama Y.
        • Kamei Y.
        • Yoshimitsu J.
        • Fujii Y.
        • et al.
        Avelumab in combination with axitinib as first-line treatment in patients with advanced hepatocellular carcinoma: results from the phase 1b VEGF liver 100 trial.
        Liver Cancer. 2021; 10: 249-259
        • Lee M.S.
        • Ryoo B.Y.
        • Hsu C.H.
        • Numata K.
        • Stein S.
        • Verret W.
        • Hack S.P.
        • Spahn J.
        • Liu B.
        • Abdullah H.
        • et al.
        Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study.
        Lancet Oncol. 2020; 21: 808-820
        • Mei K.
        • Qin S.
        • Chen Z.
        • Liu Y.
        • Wang L.
        • Zou J.
        Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib/II trial.
        J Immunother Cancer. 2021; 9
        • Ren Z.
        • Xu J.
        • Bai Y.
        • Xu A.
        • Cang S.
        • Du C.
        • Li Q.
        • Lu Y.
        • Chen Y.
        • Guo Y.
        • et al.
        Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.
        Lancet Oncol. 2021; 22: 977-990
        • Xu J.
        • Shen J.
        • Gu S.
        • Zhang Y.
        • Wu L.
        • Wu J.
        • Shao G.
        • Zhang Y.
        • Xu L.
        • Yin T.
        • et al.
        Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial.
        Clin Cancer Res. 2021; 27: 1003-1011
        • Yau T.
        • Kang Y.K.
        • Kim T.Y.
        • El-Khoueiry A.B.
        • Santoro A.
        • Sangro B.
        • Melero I.
        • Kudo M.
        • Hou M.M.
        • Matilla A.
        • 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; 6e204564
        • Faivre S.
        • Rimassa L.
        • Finn R.S.
        Molecular therapies for HCC: looking outside the box.
        J Hepatol. 2020; 72: 342-352
        • Llovet J.M.
        • Montal R.
        • Sia D.
        • Finn R.S.
        Molecular therapies and precision medicine for hepatocellular carcinoma.
        Nat Rev Clin Oncol. 2018; 15: 599-616
        • El-Serag H.B.
        • Marrero J.A.
        • Rudolph L.
        • Reddy K.R.
        Diagnosis and treatment of hepatocellular carcinoma.
        Gastroenterology. 2008; 134: 1752-1763
        • Prieto J.
        • Melero I.
        • Sangro B.
        Immunological landscape and immunotherapy of hepatocellular carcinoma.
        Nat Rev Gastroenterol Hepatol. 2015; 12: 681-700
        • Ringelhan M.
        • Pfister D.
        • O'Connor T.
        • Pikarsky E.
        • Heikenwalder M.
        The immunology of hepatocellular carcinoma.
        Nat Immunol. 2018; 19: 222-232
        • Finn R.S.
        • Ikeda M.
        • Zhu A.X.
        • Sung M.W.
        • Baron A.D.
        • Kudo M.
        • Okusaka T.
        • Kobayashi M.
        • Kumada H.
        • Kaneko S.
        • et al.
        Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.
        J Clin Oncol. 2020; 38: 2960-2970
        • Kudo M.
        Immune checkpoint inhibition in hepatocellular carcinoma: basics and ongoing clinical trials.
        Oncology. 2017; 92: 50-62
        • Hellmann M.D.
        • Paz-Ares L.
        • Bernabe Caro R.
        • Zurawski B.
        • Kim S.W.
        • Carcereny Costa E.
        • Park K.
        • Alexandru A.
        • Lupinacci L.
        • de la Mora Jimenez E.
        • et al.
        Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer.
        N Engl J Med. 2019; 381: 2020-2031
        • Motzer R.J.
        • McDermott D.F.
        • Escudier B.
        • Burotto M.
        • Choueiri T.K.
        • Hammers H.J.
        • Barthelemy P.
        • Plimack E.R.
        • Porta C.
        • George S.
        • et al.
        Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.
        Cancer. 2022;
        • Wolchok J.D.
        • Chiarion-Sileni V.
        • Gonzalez R.
        • Grob J.J.
        • Rutkowski P.
        • Lao C.D.
        • Cowey C.L.
        • Schadendorf D.
        • Wagstaff J.
        • Dummer R.
        • et al.
        Long-term outcomes with Nivolumab plus Ipilimumab or Nivolumab alone versus Ipilimumab in patients with advanced melanoma.
        J Clin Oncol. 2022; 40: 127-137
        • Torrens L.
        • Montironi C.
        • Puigvehi M.
        • Mesropian A.
        • Leslie J.
        • Haber P.K.
        • Maeda M.
        • Balaseviciute U.
        • Willoughby C.E.
        • Abril-Fornaguera J.
        • et al.
        Immunomodulatory effects of lenvatinib plus anti-programmed cell death protein 1 in mice and rationale for patient enrichment in hepatocellular carcinoma.
        Hepatology. 2021; 74: 2652-2669
        • Shigeta K.
        • Matsui A.
        • Kikuchi H.
        • Klein S.
        • Mamessier E.
        • Chen I.X.
        • Aoki S.
        • Kitahara S.
        • Inoue K.
        • Shigeta A.
        • et al.
        Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.
        J Immunother Cancer. 2020; 8
        • Yi C.
        • Chen L.
        • Lin Z.
        • Liu L.
        • Shao W.
        • Zhang R.
        • Lin J.
        • Zhang J.
        • Zhu W.
        • Jia H.
        • et al.
        Lenvatinib targets FGF receptor 4 to enhance antitumor immune response of anti-programmed cell death-1 in HCC.
        Hepatology. 2021; 74: 2544-2560
        • Benson A.B.
        • D'Angelica M.I.
        • Abbott D.E.
        • Anaya D.A.
        • Anders R.
        • Are C.
        • Bachini M.
        • Borad M.
        • Brown D.
        • Burgoyne A.
        • et al.
        Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology.
        J Natl Compr Canc Netw. 2021; 19: 541-565
        • Cillo U.
        • Vitale A.
        • Grigoletto F.
        • Farinati F.
        • Brolese A.
        • Zanus G.
        • Neri D.
        • Boccagni P.
        • Srsen N.
        • D'Amico F.
        • et al.
        Prospective validation of the Barcelona Clinic Liver Cancer staging system.
        J Hepatol. 2006; 44: 723-731
        • Zhou J.
        • Sun H.
        • Wang Z.
        • Cong W.
        • Wang J.
        • Zeng M.
        • Zhou W.
        • Bie P.
        • Liu L.
        • Wen T.
        • et al.
        Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 Edition).
        Liver Cancer. 2020; 9: 682-720