Risk factors and management of post-liver transplant recurrence of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common indications for liver transplantation (LT). With expanding criteria and increasing number of transplants, post-transplant recurrence of HCC remains an important cause for concern and portends a poor survival in these patients. Traditionally, HCC recurrence post-LT has been notoriously difficult to manage and their outcomes dismal. A better understanding of the tumour biology and its interplay with the immune system, combined with newer oncological interventions has allowed for improved survivals in these patients. A useful classification of HCC recurrence is where it is divided into oligo-recurrence and disseminated recurrence. This system helps strategize their multi-disciplinary management algorithm and prognosticate outcomes. We provide an overview of the factors which may predict recurrence and summarise the current evidence on the management of post-LT HCC recurrence.

Keywords

Hepatocellular carcinoma / post-liver transplantation / recurrence / management

References

[1] Nagai S,Kubal CA.Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: predictors for successful treatment and survival.Clin Transplant2015;29:1156-63

[2] Au KP.Multidisciplinary approach for post-liver transplant recurrence of hepatocellular carcinoma: A proposed management algorithm.World J Gastroenterol2018;24:5081-94 PMCID:PMC6288653

[3] Filgueira NA.Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation.World J Hepatol2019;11:261-72 PMCID:PMC6447422

[4] De’Angelis N,Carra MC.Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review.World J Gastroenterol2015;21:11185-98 PMCID:PMC4607916

[5] Pfiffer TEF,Nicolaou A,Riess H.Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era.Tumori2011;97:436-41

[6] Sapisochin G,Astete S.Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a Large Euro-American Series.Ann Surg Oncol2015;22:2286-94

[7] Mazzaferro V,Doci R.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med1996;334:693-9

[8] Mazzaferro V,Sposito C.Milan criteria in liver transplantation for hepatocellular carcinoma: An evidence-based analysis of 15 years of experience.Liver Transpl2011;17 Suppl 2:S44-57

[9] Germani G,Garcovich M.Which matters most: number of tumors, size of the largest tumor, or total tumor volume?.Liver Transpl2011;17 Suppl 2:S58-66

[10] Mazzaferro V,Miceli R.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol2009;10:35-43

[11] Welling TH,Carrier K.Multicenter study of staging and therapeutic predictors of hepatocellular carcinoma recurrence following transplantation.Liver Transpl2018;24:1233-42 PMCID:PMC6153067

[12] Mazzaferro V,Zhou J.Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma.Gastroenterology2018;154:128-39

[13] Nagai S,Kubal CA.Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: Predictors for successful treatment and survival.Clin Transplant2015;29:1156-63

[14] Agopian VG,Zarrinpar A.A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: Analysis of 865 consecutive liver transplant recipients.J Am Coll Surg2015;220:416-27

[15] Yao FY,Bass NM.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology2001;33:1394-403

[16] Donat M,Pereira F.Impact of histological factors of hepatocellular carcinoma on the outcome of liver transplantation.Transplant Proc2016;48:1968-77

[17] Court CM,Markovic D.Determination of hepatocellular carcinoma grade by needle biopsy is unreliable for liver transplant candidate selection.Liver Transplant2017;23:1123-32

[18] Palmirotta R,Cafforio P.Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology.Ther Adv Med Oncol2018;10:1758835918794630 PMCID:PMC6116068

[19] Llovet JM,Sia D.Molecular therapies and precision medicine for hepatocellular carcinoma.Nat Rev Clin Oncol2018;15:599-616

[20] von Felden J,Krech T.Circulating tumor cells as liquid biomarker for high HCC recurrence risk after curative liver resection.Oncotarget2017;8:89978-87 PMCID:PMC5685725

[21] Wang P,Sun Y.Detection of circulating tumour cells enables early recurrence prediction in hepatocellular carcinoma patients undergoing liver transplantation.Liver Int2021;41:562-73

[22] Sun YF,Yang XR.Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection.Hepatology2013;57:1458-68

[23] Schulze K,Staufer K.Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma.Int J Cancer2013;133:2165-71

[24] Long G,Su W,Zhou L.The prognostic value of postoperative circulating cell-free DNA in operable hepatocellular carcinoma.Scand J Gastroenterol2020;55:1441-6

[25] Wang D,Long G,Wang ZM.The clinical value of total plasma cell-free DNA in hepatitis B virus-related hepatocellular carcinoma.Ann Transl Med2019;7:650 PMCID:PMC6944585

[26] Yan L,Zhou J,Zhang H.Diagnostic value of circulating cell-free DNA levels for hepatocellular carcinoma.Int J Infect Dis2018;67:92-7

[27] Mezzalira S,Guardascione M,Cecchin E.Circulating-free DNA analysis in hepatocellular carcinoma: a promising strategy to improve patients’ management and therapy outcomes.Int J Mol Sci2019;20:5498 PMCID:PMC6861910

[28] Alunni-Fabbroni M,Huber T.Circulating DNA as prognostic biomarker in patients with advanced hepatocellular carcinoma: A translational exploratory study from the SORAMIC trial.J Transl Med2019;17:328 PMCID:PMC6771167

[29] Hameed B,Sapisochin G,Yao FY.Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.Liver Transpl2014;20:945-51 PMCID:PMC4807739

[30] Wu TH,Cheng CH.Outcomes associated with the intention of loco-regional therapy prior to living donor liver transplantation for hepatocellular carcinoma.World J Gastrointest Surg2020;12:17-27 PMCID:PMC6943093

[31] Grąt M,Stypułkowski J.Prognostic relevance of a complete pathologic response in liver transplantation for hepatocellular carcinoma.Ann Surg Oncol2019;26:4556-65 PMCID:PMC6863942

[32] Pompili M,Ponziani FR,Avolio AW.Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation.World J Gastroenterol2013;19:7515-30 PMCID:PMC3837250

[33] Merani S,Kneteman NM.The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma.J Hepatol2011;55:814-9

[34] Fung J,Tanaka Y.Quantitative hepatitis B surface antigen in predicting recurrence of hepatitis B-related hepatocellular carcinoma after liver transplantation.Hepatoma Res2018;4:62

[35] Faria LC,Roque-Afonso AM.Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation.Gastroenterology2008;134:1890-9

[36] Nahon P,Bourcier V.ANRS CO12 CirVir GroupIncidence of hepatocellular carcinoma after direct antiviral therapy for hcv in patients with cirrhosis included in surveillance programs.Gastroenterology2018;155:1436-50.e6

[37] ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts)Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts.J Hepatol2016;65:734-40

[38] Kolly P.A strong message is needed to address the issue of HCC recurrence after DAA therapy.J Hepatol2016;65:1268-9

[39] Kohli V,Elliott L.Antiviral therapy for recurrent hepatitis C reduces recurrence of hepatocellular carcinoma following liver transplantation.Transpl Int2012;25:192-200

[40] Bozorgzadeh A,Abt P.Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis.Liver Transpl2007;13:807-13

[41] Vidal RIO,Pereira BB.Risk factors for hepatocellular carcinoma recurrence and survival after liver transplantation in patients with hcv-related cirrhosis.Biomed Res Int2020;2020:1487593 PMCID:PMC7591978

[42] Zanetto A,Vitale A.Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals.Liver Transplant2017;23:1103-12

[43] Siegel AB,Wang S.Diabetes, body mass index, and outcomes in hepatocellular carcinoma patients undergoing liver transplantation.Transplantation2012;94:539-43 PMCID:PMC3605709

[44] Sadler EM,Bhat M.Liver transplantation for NASH-related hepatocellular carcinoma versus Non-NASH etiologies of hepatocellular carcinoma.Transplantation2018;102:640-7

[45] Lewin SM,Kelley RK,Yao FY.Liver transplantation recipients with nonalcoholic steatohepatitis have lower risk hepatocellular carcinoma.Liver Transplant2017;23:1015-22

[46] Schlansky B,Scott DL,Naugler WE.Waiting time predicts survival after liver transplantation for hepatocellular carcinoma: a cohort study using the United Network for Organ Sharing registry.Liver Transpl2014;20:1045-56

[47] Mehta N,Lee D.Wait time of less than 6 and greater than 18 months predicts hepatocellular carcinoma recurrence after liver transplantation: proposing a wait time “sweet Spot”.Transplantation2017;101:2071-8 PMCID:PMC5568965

[48] Agopian VG,Ruiz RM.Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within Milan criteria undergoing liver transplantation: analysis of 3601 patients from the US Multicenter HCC Transplant Consortium.Ann Surg2017;266:525-35

[49] Xu M,Banan B.Neoadjuvant locoregional therapy and recurrent hepatocellular carcinoma after liver transplantation.J Am Coll Surg2017;225:28-40 PMCID:PMC5777313

[50] Clavien PA,Bossuyt PMM,Langer B.OLT for HCC Consensus GroupRecommendations for liver transplantation for hepatocellular carcinoma: An international consensus conference report.Lancet Oncol2012;13e11-22 PMCID:PMC3417764

[51] Nagai S,Facciuto M.Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation.Hepatology2015;61:895-904

[52] Vagefi PA,Yao FY.Potential role of the donor in hepatocellular carcinoma recurrence after liver transplantation.Liver Transpl2015;21:187-94 PMCID:PMC4308564

[53] Kornberg A,Kornberg J,Thrum K.Extended ischemia times promote risk of HCC recurrence in liver transplant patients.Dig Dis Sci2015;60:2832-9

[54] Mangus RS,Vianna RM,Jones DT.Use of the piggyback hepatectomy technique in liver transplant recipients with hepatocellular carcinoma.Transplantation2008;85:1496-9

[55] Grat M,Lewandowski Z.The impact of surgical technique on the results of liver transplantation in patients with hepatocellular carcinoma.Ann Transplant2013;18:448-59

[56] Moon DB,Hwang S.No-touch en bloc right lobe living-donor liver transplantation with inferior vena cava replacement for hepatocellular carcinoma close to retrohepatic inferior vena cava: case report.Transplant Proc2013;45:3135-9

[57] Matsuda H,Shinoura S.Aggressive combined resection of hepatic inferior vena cava, with replacement by a ringed expanded polytetrafluoroethylene graft, in living-donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria.J Hepatobiliary Pancreat Sci2010;17:719-24

[58] Kulik LM,Rodrigo DR.Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.Am J Transplant2012;12:2997-3007 PMCID:PMC3523685

[59] Grant RC,Dixon PR,Grant DR.Living vs. deceased donor liver transplantation for hepatocellular carcinoma: A systematic review and meta-analysis.Clin Transplant2013;27:140-7

[60] Wong TCL,Fung JYY.Long-term survival outcome between living donor and deceased donor liver transplant for hepatocellular carcinoma: intention-to-treat and propensity score matching analyses.Ann Surg Oncol2019;26:1454-62

[61] Xiao GQ,Shen S,Yan LN.Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation.World J Gastroenterol2014;20:10953-9 PMCID:PMC4138476

[62] Lin CC.Living donor liver transplantation for hepatocellular carcinoma achieves better outcomes.HepatoBiliary Surg Nutr2016;5:415-21 PMCID:PMC5075822

[63] Pomfret EA.Killing two birds with one stone: Antineoplastic immunosuppression.Transplantation2016;100:14-5

[64] Rodríguez-Perálvarez M,Naveas MC.Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma.J Hepatol2013;59:1193-9

[65] Vivarelli M,La Barba G.Liver transplantation for hepatocellular carcinoma under calcineurin inhibitors: reassessment of risk factors for tumor recurrence.Ann Surg2008;248:857-62

[66] Menon KV,Heaton ND.Meta-analysis: rescurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma.Aliment Pharmacol Ther2013;37:411-9

[67] Cholongitas E,Rodríguez-Castro KI.Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review.Transpl Int2014;27:1039-49

[68] Geissler EK,Zölke C.Sirolimus use in liver transplant recipients with Hepatocellular carcinoma: a randomized, Multicenter, open-label phase 3 Trial.Transplantation2016;100:116-25 PMCID:PMC4683033

[69] Bodzin AS,Markovic D,Busuttil RW.Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics.Anna Surg2017;266:118-25

[70] Xie DY,Zhou J,Gao Q.2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights.Hepatobiliary Surg Nutr2020;9:452-63 PMCID:PMC7423548

[71] Moris D,McElroy L.Using hepatocellular carcinoma tumor burden score to stratify prognosis after liver transplantation.Cancers (Basel)2020;12:1-9 PMCID:PMC7697953

[72] Mehta N,Harnois DM.Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant.JAMA Oncol2017;3:493-500 PMCID:PMC5395317

[73] Ho CL,Yeung DWC.Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma.J Nucl Med2007;48:902-9

[74] Cheung TT,Lo CM.11C-acetate and 18F-FDG PET/CT for clinical staging and selection of patients with hepatocellular carcinoma for liver transplantation on the basis of milan criteria: Surgeon’s perspective.J Nucl Med2013;54:192-200

[75] Lu RC,Gao WT.Positron-emission tomography for hepatocellular carcinoma: Current status and future prospects.World J Gastroenterol2019;25:4682-95 PMCID:PMC6718031

[76] Park JW,Seok KK.A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma.J Nucl Med2008;49:1912-21

[77] Niibe Y.Oligometastases and oligo-recurrence: the new era of cancer therapy.Jpn J Clin Oncol2010;40:107-11 PMCID:PMC2813545

[78] Hellman S.Oligometastases.J Clin Oncol1995;13:8-10

[79] Hwang S,Kim DK.Resection of pulmonary metastases from hepatocellular carcinoma following liver transplantation.World J Surg2012;36:1592-602

[80] Xiang ZW,Li GH,Huang JH.Progress in the treatment of pulmonary metastases after liver transplantation for hepatocellular carcinoma.World J Hepatol2015;7:2309-14 PMCID:PMC4568491

[81] Sahgal A,Chang EL.Stereotactic body radiosurgery for spinal metastases: a critical review.Int J Radiat Oncol Biol Phys2008;71:652-65

[82] Aoki M,Kawaguchi H.Stereotactic body radiotherapy for lung metastases as oligo-recurrence: A single institutional study.J Radiat Res2016;57:55-61 PMCID:PMC4708917

[83] Ni JY,Xu LF,Chen YT.Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol2013;19:3872-82 PMCID:PMC3699038

[84] Yuan H,Li X,Wang M.Clinical efficacy of chemoembolization with simultaneous radiofrequency ablation for treatment of adrenal metastases from hepatocellular carcinoma.Cancer Imaging2018;18:24 PMCID:PMC6069544

[85] Fowler AM,Kim SK.Adrenal artery embolization: Anatomy, indications, and technical considerations.Am J Roentgenol2013;201:190-201

[86] Abdelaziz AO,Abdelmaksoud AH.De-novo versus recurrent hepatocellular carcinoma following direct-acting antiviral therapy for hepatitis C virus.Eur J Gastroenterol Hepatol2018;30:39-43

[87] Marangoni G,Sethi H,Muiesan P.Liver resection in liver transplant recipients.Hepatobiliary Pancreat Dis Int2008;7:590-4

[88] Sommacale D,Sauvanet A.Liver resection in transplanted patients: a single-center Western experience.Transplant Pro2013;45:2726-8

[89] Huang J,Wu H,Liao M.Is radiofrequency ablation applicable for recurrent hepatocellular carcinoma after liver transplantation?.J Surg Res2015;200:122-30

[90] Ko HK,Hyun KY.Tumor response to transcatheter arterial chemoembolization in recurrent hepatocellular carcinoma after living donor liver transplantation.Korean J Radiol2007;8:320-7 PMCID:PMC2627154

[91] Rammohan A.Embolization of liver tumors: past, present and future.World J Radiol2012;4:405 PMCID:PMC3460228

[92] Walton M,Claxton L.Selective internal radiation therapies for unresectable early-, intermediate-or advanced-stage hepatocellular carcinoma: Systematic review, network meta-analysis and economic evaluation.Health Technol Assess (Rockv)2020;24:1-263 PMCID:PMC7569721

[93] Salem R,Mulcahy MF.Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology2010;138:52-64

[94] Lin HS,Gao LH,Shan RF.Adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma: a systematic review and a meta-analysis.Hepatobiliary Pancreat Dis Int2015;14:236-45

[95] Zhou B,Zhu KS.Chemoembolization with Lobaplatin mixed with iodized oil for unresectable recurrent hepatocellular carcinoma after orthotopic liver transplantation.J Vasc Interv Radiol2010;21:333-8

[96] Carr BI.Hepatic artery chemoembolization for hepatocellular carcinoma recurrence confined to the transplanted liver.Case Rep Oncol2012;5:506-10 PMCID:PMC3493104

[97] Rivera L,Miller W.Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report.World J Gastroenterol2006;12:5729-32 PMCID:PMC4088179

[98] Au KP,Chan ACY,Lo CM.Initial experience with stereotactic body radiotherapy for intrahepatic hepatocellular carcinoma recurrence after liver transplantation.World J Clin cases2020;8:2758-68 PMCID:PMC7360706

[99] Lee JO,Lim JH.Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation.J Gastroenterol Hepatol2009;24:800-5

[100] Lee J,Kim WS.Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma.Cancer Chemother Pharmacol2004;54:385-90

[101] Kim HR,Rha SY.Treatment of recurrent hepatocellular carcinoma after liver transplantation.Asia Pac J Clin Oncol2011;7:258-69

[102] Llovet JM,Mazzaferro V.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[103] Yoon DH,Ryu MH.Sorafenib for recurrent hepatocellular carcinoma after liver transplantation.Jpn J Clin Oncol2010;40:768-73

[104] Galle PR.Sorafenib in advanced hepatocellular carcinoma - we have won a battle not the war.J Hepatol2008;49:871-3

[105] Bruix J,Merle P.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet2017;389:56-66

[106] Pelosof L,Casak S.Benefit-risk summary of regorafenib for the treatment of patients with advanced hepatocellular carcinoma that has progressed on sorafenib.Oncologist2018;23:496-500 PMCID:PMC5896719

[107] Heo YA.Regorafenib: a review in hepatocellular carcinoma.Drugs2018;78:951-8

[108] Finn RS,Granito A.Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial.J Hepatol2018;69:353-8

[109] Iavarone M,Czauderna C.Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.Am J Transplant2019;19:3176-84

[110] Yamashita T,Ikeda K.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 Gastroenterol2020;55:113-22 PMCID:PMC6942573

[111] Reig M.Lenvatinib: can a non-inferiority trial change clinical practice?.Lancet2018;391:1123-4

[112] 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

[113] Piñero F,Marín JI.Lenvatinib as first-line therapy for recurrent hepatocellular carcinoma after liver transplantation: is the current evidence applicable to these patients?.World J Transplant2020;10:297-306 PMCID:PMC7708877

[114] Lenvatinib following liver transplantation in patients with high-risk hepatocellular carcinoma. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT04168944. [Last accessed on 25 Feb 2021]

[115] Abou-Alfa GK,Cheng AL.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med2018;379:54-63 PMCID:PMC7523244

[116] Allaire M.Cabozantinib and the moving field of systemic treatments in advanced hepatocellular carcinoma.HepatoBiliary Surg Nutr2019;8:53-5 PMCID:PMC6383024

[117] Personeni N,Pressiani T,Santoro A.Cabozantinib for the treatment of hepatocellular carcinoma.Expert Rev Anticancer Ther2019;19:847-55

[118] Cabozantinib to treat recurrent liver cancer post transplant. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT04204850. [Last accessed on 25 Feb 2021]

[119] Tagliamonte M,Tornesello ML,Buonaguro FM.Combinatorial immunotherapy strategies for hepatocellular carcinoma.Curr Opin Immunol2016;39:103-13

[120] Prieto J,Sangro B.Immunological landscape and immunotherapy of hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol2015;12:681-700

[121] Ringelhan M,O’Connor T,Heikenwalder M.The immunology of hepatocellular carcinoma review-article.Nat Immunol2018;19:222-32

[122] Tsuchiya N,Endo I,Nakatsura T.Potentiality of immunotherapy against hepatocellular carcinoma.World J Gastroenterol2015;21:10314-26 PMCID:PMC4579878

[123] Rammohan A.Pembrolizumab for advanced hepatocellular carcinoma: tunnel at the end of the light.Dig Med Res2018;1:10

[124] Varkaris A,Nugent FW.Preserved liver transplant after pd-1 pathway inhibitor for hepatocellular carcinoma.Am J Gastroenterol2017;112:1895-6

[125] Rammohan A,Farouk M,Rela M.Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: the silver bullet?.Hepatology2018;67:1166-8

[126] 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

[127] El-Khoueiry AB,Yau T.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet2017;389:2492-502 PMCID:PMC7539326

[128] De Martin E,Rosmorduc O,Samuel D.Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.JHEP Rep2020;2:100170 PMCID:PMC7648167

[129] Wu Z,Li M,Zhang W.Acute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer.Medicine (Baltimore)2017;96:e9431 PMCID:PMC5758274

[130] Al Jarroudi O,Almohamad W,Morere JF.Anti-programmed cell death protein 1 (pd-1) immunotherapy for metastatic hepatocellular carcinoma after liver transplantation: a report of three cases.Cureus2020;12:e11150 PMCID:PMC7586420