Neoadjuvant and adjuvant systemic treatment for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal malignancy, and few patients are candidates for curative-intended therapies. The mainstay of curative treatment in HCC is surgical resection, ablation, and transplantation. However, rates of recurrence are high, and there is no established approach to reduce the risk of recurrence and mortality. We discuss the available data and current landscape of (neo)adjuvant therapies aimed at decreasing recurrence risk and improving overall survival, including liver-directed therapies, tyrosine kinase inhibitors, and immunotherapy. Neoadjuvant strategies aimed at downstaging advanced HCC to enable local treatment and minimize the risk of recurrence using novel agents are also a topic of interest in current research. The improvements achieved in the advanced stages with immune-checkpoint inhibitors are priming ongoing trials that address potential future directions for both adjuvant and neoadjuvant strategies that may change the treatment paradigm of HCC in the near future.

Keywords

Liver neoplasm / hepatocellular carcinoma / neoadjuvant treatment / adjuvant treatment / immunotherapy

References

[1] Association for the Study of the Liver. Electronic address: [e-mail], European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[2] Hasegawa K,Makuuchi M.Comparison of resection and ablation for hepatocellular carcinoma: a cohort study based on a Japanese nationwide survey.J Hepatol2013;58:724-9

[3] Heimbach JK,Finn RS.AASLD guidelines for the treatment of hepatocellular carcinoma.Hepatology2018;67:358-80

[4] Portolani N,Ghidoni S.Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications.Ann Surg2006;243:229-35 PMCID:PMC1448919

[5] Ouyang L,Park CK.Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas.BMC Med Genomics2014;7:2 PMCID:PMC3896667

[6] Choi JH,Park YK.Mutations acquired by hepatocellular carcinoma recurrence give rise to an aggressive phenotype.Oncotarget2017;8:22903-16 PMCID:PMC5410272

[7] Okajima W,Ichikawa D.Liquid biopsy in patients with hepatocellular carcinoma: circulating tumor cells and cell-free nucleic acids.World J Gastroenterol2017;23:5650-68 PMCID:PMC5569280

[8] Ma J,Goswami S.PD1^Hi CD8⁺ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma.J Immunother Cancer2019;7:331 PMCID:PMC6884778

[9] Sun HC,Wang L.Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial.J Cancer Res Clin Oncol2006;132:458-65

[10] Zhang W,Zhang T.Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: a meta-analysis with comparison of different types of hepatitis.Mol Clin Oncol2014;2:1125-34 PMCID:PMC4179807

[11] Yin J,Han Y.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study.J Clin Oncol2013;31:3647-55

[12] Wang Z,Chen Y.Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study.Clin Cancer Res2018;24:2074-81

[13] Wei W,Li SH.Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety.Cancer Commun (Lond)2018;38:61 PMCID:PMC6235393

[14] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[15] Bruix J,Mazzaferro V.Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Oncol2015;16:1344-54

[16] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet2018;391:1163-73

[17] Bruix J,Reig M.Insights into the success and failure of systemic therapy for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2019;16:617-30

[18] Xia Y,Li J.Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial.Ann Surg Oncol2010;17:3137-44

[19] Chen K,Wang H,Xiang G.Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial.PLoS One2013;8:e57397 PMCID:PMC3585398

[20] Gabrielson A,Wang H.Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC.Cancer Immunol Res2016;4:419-30 PMCID:PMC5303359

[21] Chen DS.Combinations of bevacizumab with cancer immunotherapy.Cancer J2018;24:193-204

[22] von Felden J,Garcia-Lezana T.Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.Oncogene2021;40:140-51

[23] Brown ZJ,Heinrich B.Adjuvant treatment of hepatocellular carcinoma: prospect of immunotherapy.Hepatology2019;70:1437-42

[24] Takayama T,Makuuchi M.Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial.Lancet2000;356:802-7

[25] Lee JH,Lee Y.Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study.Oncoimmunology2017;6:e1328335 PMCID:PMC5543846

[26] Kuang M,Lu MD.Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma.Clin Cancer Res2004;10:1574-9

[27] Finn RS,Ikeda M.IMbrave150 InvestigatorsAtezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med2020;382:1894-905

[28] Yau T,Kim TY.Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: The CheckMate 040 randomized clinical trial.JAMA Oncol2020;6:e204564 PMCID:PMC7530824

[29] Zhu AX,Edeline J.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.Lancet Oncol2018;19:940-52

[30] Kudo M,Nakahira S.Adjuvant nivolumab for hepatocellular carcinoma (HCC) after surgical resection (SR) or radiofrequency ablation (RFA) (NIVOLVE): a phase 2 prospective multicenter single-arm trial and exploratory biomarker analysis.JCO2021;39:4070

[31] Liu J,Zhang Y,Lin HS.Traditional Chinese medicine and cancer: History, present situation, and development.Thorac Cancer2015;6:561-9 PMCID:PMC4567000

[32] Chen Q,Laurence AD.Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.Gut2018;67:2006-16

[33] Zhai XF,Shen F,Ling CQ.Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: a randomized controlled study.Cancer2018;124:2161-8

[34] Lencioni R,Crocetti L.Chemoembolization of hepatocellular carcinoma.Semin Intervent Radiol2013;30:3-11 PMCID:PMC3700789

[35] Jianyong L,Wentao W.Preoperative transcatheter arterial chemoembolization for resectable hepatocellular carcinoma: a single center analysis.Ann Hepatol2014;13:394-402

[36] Zhang Z,Liu Q.The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcninoma.Zhonghua Zhong Liu Za Zhi1999;21:214-6

[37] Monden M,Sakon M.Significance of transcatheter chemoembolization combined with surgical resection for hepatocellular carcinomas.Cancer Chemother Pharmacol1989;23 Suppl:S90-5

[38] Qi X,Wang D,Su C.Hepatic resection alone versus in combination with pre- and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.Oncotarget2015;6:36838-59 PMCID:PMC4742214

[39] Zhang Y,Wang Y.Is salvage liver resection necessary for initially unresectable hepatocellular carcinoma patients downstaged by transarterial chemoembolization?.Oncologist2016;21:1442-9 PMCID:PMC5153353

[40] Kallini JR,Salem R.Transarterial radioembolization with Yttrium-90 for the treatment of hepatocellular carcinoma.Adv Ther2016;33:699-714 PMCID:PMC4882351

[41] Gaba RC,Kulik LM.Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium-90 radioembolization.Ann Surg Oncol2009;16:1587-96

[42] Salem R,Kim E.Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study.Hepatology2021;

[43] Schwarz RE,Geschwind JF,Salem R.American Hepato-Pancreato-Biliary AssociationSociety of Surgical OncologySociety for Surgery of the Alimentary TractNonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement.HPB (Oxford)2010;12:313-20 PMCID:PMC2951818

[44] Li S,Li Q.Neoadjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of resectable BCLC stage A/B hepatocellular carcinoma patients beyond Milan criteria: an interim analysis of a multi-center, phase 3, randomized, controlled clinical trial.JCO2021;39:4008

[45] Marron T,Tabrizian P.Neoadjuvant cemiplimab demonstrates complete pathological responses in hepatocellular carcinoma [abstract]. Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT182.

[46] Pinato DJ,Pai M.PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.J Clin Oncol2021;39:e16131 PMCID:PMC7988931