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NAFLD-driven HCC: Safety and efficacy of current and emerging treatment options

Published:September 19, 2021DOI:https://doi.org/10.1016/j.jhep.2021.09.007

      Summary

      In light of a global rise in obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent an increasingly important underlying aetiology of hepatocellular carcinoma (HCC). HCCs arising from lipotoxicity-mediated chronic inflammation are characterised by several unique features: in contrast to virally driven HCC, up to 50% of NAFLD-HCC occurs in patients without cirrhosis and annual HCC incidence is comparatively low, complicating current surveillance strategies. On average, patients are older and are more frequently diagnosed at an advanced stage. While locoregional treatments are probably equally effective regardless of HCC aetiology, the picture is less clear for systemic therapy. Tyrosine kinase inhibitors are probably equally effective, while there have been initial signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC than in viral HCC. Current international clinical practice guidelines for HCC do not consider aetiology, as there are insufficient data to draw specific conclusions or to recommend aetiology-specific modifications to the current management of patients with HCC. However, in light of the growing relevance of NAFLD-HCC, future clinical trials should assess whether HCC aetiology – and NAFLD/NASH in particular – influence the safety and efficacy of a given treatment.

      Keywords

      Introduction

      The incidence and mortality of liver cancer have been continuously rising over the last decades. In 2020, liver cancer represented the sixth most common cancer entity worldwide with a total of 905,677 new registered cases. Despite recent advances, liver cancer is still associated with a dismal prognosis. With 830,180 deaths, liver cancer ranked third among cancer-related deaths in 2020. Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is known to be caused by a variety of risk factors. One of these is non-alcoholic fatty liver disease (NAFLD) which is caused by obesity, dyslipidaemia and type 2 diabetes mellitus. Histologically, NAFLD is characterised by hepatic steatosis of ≥5%.
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      This review article summarises current knowledge on the pathogenesis, surveillance and treatment of NAFLD-HCC. It also highlights current challenges associated with this condition and makes suggestions regarding how these challenges might be addressed.

      Pathogenesis and the immune contexture

      A comprehensive review on the pathogenesis of NAFLD and its transition to NASH and ultimately HCC has been published recently and is not within the scope of this review.
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      In general, the tumour microenvironment plays a key role in tumourigenesis and the response to different targeted therapies in a variety of cancer entities. In particular, the tumour immune microenvironment substantially influences tumour progression and prognosis.
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      The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.
      In a mouse model of choline-deficient high-fat diet-induced NASH, activation of both CD8+ T and natural killer T cells accelerated hepatic tumourigenesis.
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      Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
      Recently, Pfister et al. demonstrated that the increase of hepatic CD8+PD1+ T cells impairs immune surveillance and triggers hepatocarcinogenesis in a mouse model of NASH.
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      CD4+ T cells, in contrast, are required for efficient immune surveillance and are known to impair HCC tumourigenesis.
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      In line, the selective decrease of CD4+ T lymphocytes in MYC oncogene transgenic mice fed a methionine-choline-deficient diet drives HCC tumour development.
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      NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
      Furthermore, NAFLD-driven chronic inflammation leads to the suppression of cytotoxic CD8+ T lymphocytes by IgA+ cells, thereby disrupting immune surveillance and promoting HCC development.
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      Immune checkpoint inhibitors (ICIs) are thought to restore tumour immune surveillance by targeting the programmed cell death-1 receptor (PD1; nivolumab, pembrolizumab) on exhausted CD8+ T cells or the programmed cell death 1 ligand 1 (PD-L1, atezolizumab).
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      In addition, there is growing evidence that the gut microbiome plays a key role in the pathogenesis of NAFLD/NASH.
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      NAFLD-related cirrhosis and NAFLD-HCC are both characterised by unique gut microbiome signatures.
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      Remarkably, this appears to result in an immunosuppressive phenotype in NAFLD-HCC.
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      Prevention

      Vaccination against HBV infection as well as the treatment of chronic HBV and HCV infection with oral antiviral therapies are the mainstay for the prevention of viral HCC, which has led to a decrease in HCC risk.
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      Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan childhood hepatoma study group.
      Regarding NAFLD-driven HCC, lifestyle changes are currently the only evidence-based means of preventing or delaying the development and progression of NAFLD. A recent analysis of the European Prospective Investigation into Cancer and Nutrition cohort (EPIC; 467,336 participants) revealed a negative correlation between physical activity and the risk of HCC development.
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      Likewise, a Mediterranean diet is associated with a lower HCC risk.
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      In terms of chemoprevention, metformin (in patients with type 2 diabetes) and statins may reduce the risk of HCC development.
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      Aspirin use in patients with NAFLD was associated with a lower risk of fibrosis progression.
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      Daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease.
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      A recent propensity score matched analysis comprising 4,112 patients showed a reduction in NASH and HCC development after bariatric surgery in obese patients.
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      It is likely but remains to be seen whether medicines effective at treating NASH will also reduce the associated risk of HCC.

      Surveillance

      According to the current EASL
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      and AASLD
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      HCC guidelines, patients at high risk of developing HCC should be included in surveillance programmes, mainly consisting of ultrasound examinations at a 6-month interval with or without alpha-fetoprotein testing. Hence, surveillance should be offered to patients with Child-Pugh A and B cirrhosis, those with Child-Pugh C cirrhosis awaiting liver transplantation, and potentially to non-cirrhotic patients with hepatitis B or F3 fibrosis depending on their individual risk profile. While Barcelona Clinic Liver Cancer (BCLC) stage C represents the most frequent HCC stage at diagnosis in North America and Europe, Taiwan and Japan detect most tumours at BCLC stage A, most likely due to effective surveillance programmes, resulting in a remarkable better median overall survival (OS).
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      Regarding NAFLD/NASH, several factors hamper surveillance strategies. First, the incidence of NAFLD-HCC is lower than of viral HCC, thus reducing the cost-effectiveness of screening programmes. Second, in contrast to hepatitis B/C-associated HCC, 20%–50% of NAFLD-HCCs develop without underlying cirrhosis.
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      Third, subcutaneous fat and liver steatosis in obese patients hinder ultrasound examination.
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      NAFLD-HCC appears to differ from viral HCC with regard to pathogenesis, tumour microenvironment, time of diagnosis, clinical management, and treatment outcomes.
      A current expert review by Loomba et al. recommends surveillance for patients with NAFLD-associated advanced liver fibrosis and cirrhosis, but not for patients with NAFLD without signs of advanced liver fibrosis.
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      In case of difficult ultrasound conditions, CT or MRI scans are recommended.
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      In particular, non-enhanced MRI appears to be a suitable imaging modality due to its low time requirement, lack of contrast-agent, and increased sensitivity and specificity compared to ultrasound.
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      The current Japanese NAFLD/NASH guidelines recommend a 2-step risk stratification process including screening for serum markers of fibrosis or platelet counts, the fibrosis-4 index or the NAFLD fibrosis score.
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      • Tokushige K.
      The current view of nonalcoholic fatty liver disease-related hepatocellular carcinoma.
      Depending on the risk of fibrosis, subsequent liver elastography or biopsy is recommended. Ultrasound-based HCC screening may be performed in male patients with F2/F3 fibrosis, female patients with F3 fibrosis and in all patients with cirrhosis.
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      • Tokushige K.
      The current view of nonalcoholic fatty liver disease-related hepatocellular carcinoma.
      Until now, NAFLD-HCC is more frequently diagnosed at an advanced stage, e.g. in symptomatic individuals, owing to the lack of appropriate surveillance strategies.
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      Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
      ,
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      Treatment

      The current international guidelines recommend BCLC-based treatment algorithms, in which the underlying HCC aetiology does not influence treatment recommendations.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.
      In fact, little is known about the impact of NAFLD as an aetiology on the treatment outcome of patients with HCC (summarised in Table 1). In general, impaired liver function because of cirrhosis limits curative treatment options in many patients with HCC. Regarding NAFLD-HCC, metabolic syndrome-associated comorbidities, older age and frequent diagnosis at an advanced stage further hamper oncological management.
      • Anstee Q.M.
      • Reeves H.L.
      • Kotsiliti E.
      • Govaere O.
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      ,
      • Mohamad B.
      • Shah V.
      • Onyshchenko M.
      • Elshamy M.
      • Aucejo F.
      • Lopez R.
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      Characterization of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis.
      Consequently, curative treatment approaches are less likely to be indicated in patients with NAFLD compared to those with non-NAFLD aetiologies.
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      • Nguyen A.
      • Lim J.K.
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      However, beyond the clinical challenges associated with impaired liver function, a data-mining analysis has demonstrated that a subgroup of patients with NAFLD-HCC and serum albumin levels ≥3.7 g/dl, who underwent hepatic resection or radiofrequency ablation (RFA) with curative intent, had the best prognosis.
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      Table 1Overview of different treatment modalities and a comparison of outcomes in patients with NAFLD-HCC and non-NAFLD-HCC.
      TreatmentOutcome in patients with NAFLD-HCC compared to non-NAFLD-HCCQuality of evidenceSource(s)
      Liver resectionBetterRetrospective analyses and meta-analysisBetter OS
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      ,
      • Koh Y.X.
      • Tan H.J.
      • Liew Y.X.
      • Syn N.
      • Teo J.Y.
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      Diabetes mellitus and/or nonalcoholic steatohepatitis-related hepatocellular carcinoma showed favorable surgical outcomes after hepatectomy.
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      • Fava C.
      • Capelli P.
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      Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC.
      ,
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      • Samra P.-B.
      • Liu H.
      • Wessel C.
      • Lou Klem M.
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      Hepatic resection for hepatocellular carcinoma in nonalcoholic fatty liver disease.
      ; Similar OS
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      • Goumard C.
      • Scatton O.
      • Wendum D.
      • Rosmorduc O.
      • et al.
      Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period.
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      • Lemekhova A.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.
      • Yang T.
      • Hu L.-Y.
      • Li Z.-L.
      • Liu K.
      • Wu H.
      • Xing H.
      • et al.
      Liver resection for hepatocellular carcinoma in non-alcoholic fatty liver disease: a multicenter propensity matching analysis with HBV-HCC.
      • Wakai T.
      • Shirai Y.
      • Sakata J.
      • Korita P.V.
      • Ajioka Y.
      • Hatakeyama K.
      Surgical outcomes for hepatocellular carcinoma in nonalcoholic fatty liver disease.
      Liver transplantationProbably similarRetrospective analyses and registry studiesSimilar OS
      • Reddy S.K.
      • Steel J.L.
      • Chen H.-W.
      • DeMateo D.J.
      • Cardinal J.
      • Behari J.
      • et al.
      Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.
      ,
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • Perumpail R.B.
      • Harrison S.A.
      • Younossi Z.M.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      ,
      • Haldar D.
      • Kern B.
      • Hodson J.
      • Armstrong M.J.
      • Adam R.
      • Berlakovich G.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      Haldar et al.73: worse OS of NAFLD-HCC compared to ALD-HCC, similar OS compared to HCV- or cryptogenic HCC.
      ; Worse OS
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      AblationProbably similar
      Applies to radiofrequency ablation – no data available for microwave ablation.
      Retrospective analysisSimilar OS
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      Transarterial chemoembolizationProbably similarRetrospective analysisSimilar OS
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • Hall D.
      • Roller L.
      • Charaf Y.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      Selective internal radiation therapyProbably similarRetrospective analysisSimilar OS
      • Schotten C.
      • Bechmann L.P.
      • Manka P.
      • Theysohn J.
      • Dechêne A.
      • El Fouly A.
      • et al.
      NAFLD-associated comorbidities in advanced stage HCC do not alter the safety and efficacy of yttrium-90 radioembolization.
      Stereotactic body radiation therapyn.a.n.a.n.a.
      Tyrosine kinase inhibitorsProbably similar
      Applies to sorafenib.
      Cohort studySimilar
      • Howell J.
      • Samani A.
      • Mannan B.
      • Hajiev S.
      • Aval L.M.
      • Abdelmalak R.
      • et al.
      Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study.
      Checkpoint inhibitorsPotentially worsePost hoc analysis and meta-analysisNo benefit/worse
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
      ALD, alcohol-related liver disease; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; OS, overall survival.
      Applies to radiofrequency ablation – no data available for microwave ablation.
      ∗∗ Haldar et al.
      • Haldar D.
      • Kern B.
      • Hodson J.
      • Armstrong M.J.
      • Adam R.
      • Berlakovich G.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      : worse OS of NAFLD-HCC compared to ALD-HCC, similar OS compared to HCV- or cryptogenic HCC.
      ∗∗∗ Applies to sorafenib.

      Hepatic resection

      Liver resection represents standard-of-care for patients with HCC without cirrhosis.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.
      Data from studies comparing outcomes after hepatic resection in patients with NAFLD-HCC or other aetiologies of HCC are inconsistent: Several studies have reported a significant OS benefit for patients with NAFLD-HCC,
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      ,
      • Koh Y.X.
      • Tan H.J.
      • Liew Y.X.
      • Syn N.
      • Teo J.Y.
      • Lee S.Y.
      • et al.
      Liver resection for nonalcoholic fatty liver disease-associated hepatocellular carcinoma.
      • Reddy S.K.
      • Steel J.L.
      • Chen H.-W.
      • DeMateo D.J.
      • Cardinal J.
      • Behari J.
      • et al.
      Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.
      • Liang J.
      • Ariizumi S.-I.
      • Nakano M.
      • Yamamoto M.
      Diabetes mellitus and/or nonalcoholic steatohepatitis-related hepatocellular carcinoma showed favorable surgical outcomes after hepatectomy.
      • Viganò L.
      • Conci S.
      • Cescon M.
      • Fava C.
      • Capelli P.
      • D'Errico A.
      • et al.
      Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC.
      • Campani C.
      • Bensi C.
      • Milani S.
      • Galli A.
      • Tarocchi M.
      Resection of NAFLD-associated HCC: patient selection and reported outcomes.
      while others have not.
      • Pais R.
      • Fartoux L.
      • Goumard C.
      • Scatton O.
      • Wendum D.
      • Rosmorduc O.
      • et al.
      Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period.
      • Billeter A.T.
      • Müller P.C.
      • Albrecht T.
      • Roessler S.
      • Löffler M.
      • Lemekhova A.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.
      • Yang T.
      • Hu L.-Y.
      • Li Z.-L.
      • Liu K.
      • Wu H.
      • Xing H.
      • et al.
      Liver resection for hepatocellular carcinoma in non-alcoholic fatty liver disease: a multicenter propensity matching analysis with HBV-HCC.
      • Wakai T.
      • Shirai Y.
      • Sakata J.
      • Korita P.V.
      • Ajioka Y.
      • Hatakeyama K.
      Surgical outcomes for hepatocellular carcinoma in nonalcoholic fatty liver disease.
      However, a recent meta-analysis of 15 studies comprising a total of 7,226 patients reported that patients with NAFLD-HCC had improved disease-free survival and OS after hepatic resection compared to patients with other aetiologies.
      • Molinari M.
      • Kaltenmeier C.
      • Samra P.-B.
      • Liu H.
      • Wessel C.
      • Lou Klem M.
      • et al.
      Hepatic resection for hepatocellular carcinoma in nonalcoholic fatty liver disease.
      In particular, metabolic syndrome-associated cardiovascular comorbidities have to be evaluated carefully in terms of patient selection for major surgery.
      • Kaufmann B.
      • Reca A.
      • Wang B.
      • Friess H.
      • Feldstein A.E.
      • Hartmann D.
      Mechanisms of nonalcoholic fatty liver disease and implications for surgery.
      While recurrence rates were lower in patients with NAFLD-HCC (44.6%) compared to HCV-HCC (65.2%),
      • Viganò L.
      • Conci S.
      • Cescon M.
      • Fava C.
      • Capelli P.
      • D'Errico A.
      • et al.
      Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC.
      another study found that patients with non-cirrhotic NASH face a similarly high risk of HCC recurrence as patients with cirrhosis due to other aetiologies.
      • Billeter A.T.
      • Müller P.C.
      • Albrecht T.
      • Roessler S.
      • Löffler M.
      • Lemekhova A.
      • et al.
      Impact of type 2 diabetes on oncologic outcomes of hepatocellular carcinomas in non-cirrhotic, non-alcoholic steatohepatitis: a matched-pair analysis.
      However, with a 90-day mortality rate of 11% and major complications occurring in 31%, hepatic resection in NAFLD-HCC carries a significant postoperative mortality/morbidity burden.
      • Cauchy F.
      • Zalinski S.
      • Dokmak S.
      • Fuks D.
      • Farges O.
      • Castera L.
      • et al.
      Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome.
      Remarkably, patients with NAFLD-HCC face higher rates of postsurgical complications than patients with non-NAFLD-HCC.
      • Koh Y.X.
      • Tan H.J.
      • Liew Y.X.
      • Syn N.
      • Teo J.Y.
      • Lee S.Y.
      • et al.
      Liver resection for nonalcoholic fatty liver disease-associated hepatocellular carcinoma.
      ,
      • Wakai T.
      • Shirai Y.
      • Sakata J.
      • Korita P.V.
      • Ajioka Y.
      • Hatakeyama K.
      Surgical outcomes for hepatocellular carcinoma in nonalcoholic fatty liver disease.
      Hepatic resection in patients with cirrhosis is mainly limited to “optimal surgical candidates” (for example single tumour nodule, preserved liver function, platelet counts >100,000/ml, hepatic venous pressure gradient <10 mmHg).
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      However, patient stratification tools predicting the risk of postoperative hepatic decompensation, including portal hypertension, extension of resection and model for end-stage liver disease score, can extend the patient cohort amenable to surgical resection despite cirrhosis.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Citterio D.
      • Facciorusso A.
      • Sposito C.
      • Rota R.
      • Bhoori S.
      • Mazzaferro V.
      Hierarchic interaction of factors associated with liver decompensation after resection for hepatocellular carcinoma.
      Patients with NAFLD-HCC receiving hepatic resection appear to have improved disease-free and overall survival compared with other underlying aetiologies.

      Liver transplantation

      Liver transplantation (LT) is recommended as the treatment of choice for patients with cirrhosis and HCC, who meet the Milan criteria, and for whom primary surgical resection is not an option.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.
      ,
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      The 10-year-survival rate after LT due to cancer is currently 51% according to the European Liver Transplant Registry.

      European Liver Transplant Registry. Patient survival vs. Primary disease; Available from: https://www.eltr.org/Overall-indication-and-results.html.

      However, LT is limited by donor organ shortages. Currently, NAFLD/NASH represents the second most frequent indication for LT after HCV in the US and is expected to become the most frequent one.
      • Wong R.J.
      • Aguilar M.
      • Cheung R.
      • Perumpail R.B.
      • Harrison S.A.
      • Younossi Z.M.
      • et al.
      Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
      • Cholankeril G.
      • Wong R.J.
      • Hu M.
      • Perumpail R.B.
      • Yoo E.R.
      • Puri P.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes.
      • Younossi Z.M.
      Non-alcoholic fatty liver disease - a global public health perspective.
      Patients undergoing LT because of NASH face a higher risk of intraoperative (extended operative time, higher blood loss) and postoperative complications (longer postoperative hospitalisation, more frequent cardiovascular events).
      • Agopian V.G.
      • Kaldas F.M.
      • Hong J.C.
      • Whittaker M.
      • Holt C.
      • Rana A.
      • et al.
      Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.
      ,
      • Vanwagner L.B.
      • Bhave M.
      • Te H.S.
      • Feinglass J.
      • Alvarez L.
      • Rinella M.E.
      Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events.
      Data from studies comparing long-term outcomes after LT in patients with NAFLD-HCC or other aetiologies of HCC are inconsistent: an analysis of the United Network for Organ Sharing registry between 2002 to 2012 yielded comparable 5-year OS rates for NASH-, HCV-, and alcohol-driven HCC (65.5%, 65.7%, 63.9%, respectively).
      • Wong R.J.
      • Chou C.
      • Bonham C.A.
      • Concepcion W.
      • Esquivel C.O.
      • Ahmed A.
      Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data.
      Similarly, Reddy et al. reported no significant OS differences between NASH- and HCV/alcohol-driven HCC after LT.
      • Reddy S.K.
      • Steel J.L.
      • Chen H.-W.
      • DeMateo D.J.
      • Cardinal J.
      • Behari J.
      • et al.
      Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.
      However, Wong et al. found a reduced OS for patients with NAFLD-HCC compared to non-NASH-HCC.
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      A European Liver Transplant Registry analysis comprising nearly 69,000 LT recipients between 2002 and 2016 reported a slightly reduced OS for NAFLD-HCC compared to alcohol-driven HCC and no differences compared to HCV- or cryptogenic cirrhosis (10-year survival rates: 46.9%, 51.8%, 48.2% and 52.9%, respectively).
      • Haldar D.
      • Kern B.
      • Hodson J.
      • Armstrong M.J.
      • Adam R.
      • Berlakovich G.
      • et al.
      Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study.
      In summary, patients with NAFLD-HCC undergoing LT appear to have similar post-transplant outcomes as patients with other aetiologies of HCC despite an increased short-term postoperative risk.
      • Geh D.
      • Manas D.M.
      • Reeves H.L.
      Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians.

      Ablation

      Alternating current-induced RFA is recommended for BCLC 0- or A-staged patients not amenable to surgery.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      For tumours <2 cm (BCLC 0), primary RFA yielded similar OS rates as primary hepatic resection according to a Markov model-based analysis and therefore may be applied as first-line therapy for this cohort.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Cho Y.K.
      • Kim J.K.
      • Kim W.T.
      • Chung J.W.
      Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.
      An American retrospective study found no differences regarding OS in RFA-treated patients with NAFLD-HCC compared to those with other underlying HCC aetiologies.
      • Wong C.R.
      • Njei B.
      • Nguyen M.H.
      • Nguyen A.
      • Lim J.K.
      Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non-alcoholic fatty liver disease.
      Type 2 diabetes in patients with HCC undergoing RFA is associated with reduced OS.
      • Chen T.-M.
      • Lin C.-C.
      • Huang P.-T.
      • Wen C.-F.
      Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation.
      Remarkably, metformin therapy correlated positively with OS within this patient cohort.
      • Chen T.-M.
      • Lin C.-C.
      • Huang P.-T.
      • Wen C.-F.
      Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation.
      Microwave ablation (MWA) represents an alternative therapeutic approach to RFA with comparable results in terms of efficacy and safety.
      • Facciorusso A.
      • Di Maso M.
      • Muscatiello N.
      Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.
      MWA appears to be more beneficial in patients with larger tumour nodules with regard to local recurrence rates.
      • Facciorusso A.
      • Di Maso M.
      • Muscatiello N.
      Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.
      However, data on the efficacy of MWA in NAFLD-driven HCC are lacking.

      Neoadjuvant and adjuvant therapies

      For patients who have received treatment with curative intent, HCC recurrence is the most prognostically important event. It occurs in up to 70% of patients within 5 years after hepatic resection or after ablation.
      • N'Kontchou G.
      • Mahamoudi A.
      • Aout M.
      • Ganne-Carrié N.
      • Grando V.
      • Coderc E.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis.
      • Roayaie S.
      • Obeidat K.
      • Sposito C.
      • Mariani L.
      • Bhoori S.
      • Pellegrinelli A.
      • et al.
      Resection of hepatocellular cancer ≤2 cm: results from two Western centers.
      • Tabrizian P.
      • Jibara G.
      • Shrager B.
      • Schwartz M.
      • Roayaie S.
      Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis.
      • Kim Y.
      • Rhim H.
      • Cho O.K.
      • Koh B.H.
      • Kim Y.
      Intrahepatic recurrence after percutaneous radiofrequency ablation of hepatocellular carcinoma: analysis of the pattern and risk factors.
      • Majumdar A.
      • Roccarina D.
      • Thorburn D.
      • Davidson B.R.
      • Tsochatzis E.
      • Gurusamy K.S.
      Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis.
      Effective neoadjuvant and adjuvant therapies are still lacking and are consequently not recommended by current guidelines regardless of HCC aetiology.
      The STORM trial found no significant survival benefit for adjuvant treatment with sorafenib after liver resection or ablation.
      • Bruix J.
      • Takayama T.
      • Mazzaferro V.
      • Chau G.-Y.
      • Yang J.
      • Kudo M.
      • et al.
      Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.
      Adjuvant adoptive immunotherapy after liver resection extended recurrence-free survival (RFS) by 12 months but did not influence OS.
      • Takayama T.
      • Sekine T.
      • Makuuchi M.
      • Yamasaki S.
      • Kosuge T.
      • Yamamoto J.
      • et al.
      Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial.
      Adjuvant therapy with activated cytokine-induced killer cells slightly improved both RFS and OS in a phase III trial.
      • Lee J.H.
      • Lee J.-H.
      • Lim Y.-S.
      • Yeon J.E.
      • Song T.-J.
      • Yu S.J.
      • et al.
      Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma.
      In a high-risk setting for recurrence, prematurely listing patients for LT after hepatic resection but prior to recurrence was associated with a 5-year-survival rate of 82.4%, which is unusually high.
      • Ferrer-Fàbrega J.
      • Forner A.
      • Liccioni A.
      • Miquel R.
      • Molina V.
      • Navasa M.
      • et al.
      Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection.
      However, the study’s sample size was small (n = 85) and it was neither randomised nor controlled.
      Four ongoing phase III trials are currently testing the efficacy of nivolumab (CheckMate 9DX, NCT03383458), pembrolizumab (KEYNOTE-937, NCT03867084), atezolizumab plus bevacizumab (IMbrave-050, NCT04102098) and durvalumab +/- bevacizumab (EMERALD-2, NCT03847428) in the adjuvant setting after curative treatment.
      • Llovet J.M.
      • Kelley R.K.
      • Villanueva A.
      • Singal A.G.
      • Pikarsky E.
      • Roayaie S.
      • et al.
      Hepatocellular carcinoma.

      External radiation therapy/stereotactic body radiation therapy

      Through continuous technical improvements, external radiation therapy has become an alternative treatment option for patients with HCC.
      • Marrero J.A.
      • Kulik L.M.
      • Sirlin C.B.
      • Zhu A.X.
      • Finn R.S.
      • Abecassis M.M.
      • et al.
      Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.
      ,
      • Bang A.
      • Dawson L.A.
      Radiotherapy for HCC: ready for prime time?.
      ,
      • Yacoub J.H.
      • Mauro D.
      • Moon A.
      • He A.R.
      • Bashir M.R.
      • Hsu C.C.
      • et al.
      Therapies for hepatocellular carcinoma: overview, clinical indications, and comparative outcome evaluation. Part two: noncurative intention.
      Several investigations have shown promising results for stereotactic body radiation therapy (SBRT) for patients with high local tumour burden and macrovascular infiltration. Regarding the safety and efficacy of SBRT, the specific reporting of patients with NAFLD-associated HCC in the few available studies is scarce and studies focusing on the role of SBRT in this particular aetiology are missing.
      • Feng M.
      • Suresh K.
      • Schipper M.J.
      • Bazzi L.
      • Ben-Josef E.
      • Matuszak M.M.
      • et al.
      Individualized adaptive stereotactic body radiotherapy for liver tumors in patients at high risk for liver damage: a phase 2 clinical trial.

      Transarterial chemoembolisation

      According to current guidelines, transarterial chemoembolisation (TACE) is the treatment of choice for patients within the intermediate stage (BCLC B).
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      Although TACE in intermediate stage is well investigated, literature on its efficacy and safety in NAFLD-HCC is scarce. While several studies cursorily mention TACE as a safe and feasible treatment option for these patients,
      • Siriwardana R.C.
      • Niriella M.A.
      • Dassanayake A.S.
      • Liyanage C.A.H.
      • Upasena A.
      • Sirigampala C.
      • et al.
      Factors affecting post-embolization fever and liver failure after trans-arterial chemo-embolization in a cohort without background infective hepatitis- a prospective analysis.
      ,
      • Weinmann A.
      • Alt Y.
      • Koch S.
      • Nelles C.
      • Düber C.
      • Lang H.
      • et al.
      Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma.
      only 1 retrospective head-to-head comparison of patients with NAFLD-HCC and other aetiologies of HCC is available.
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • Hall D.
      • Roller L.
      • Charaf Y.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      In this study, Young et al. did not find a significant difference in time-to-progression or median OS after TACE. Additionally, the number of complications did not differ.
      • Young S.
      • Sanghvi T.
      • Rubin N.
      • Hall D.
      • Roller L.
      • Charaf Y.
      • et al.
      Transarterial chemoembolization of hepatocellular carcinoma: propensity score matching study comparing survival and complications in patients with nonalcoholic steatohepatitis versus other causes cirrhosis.
      In contrast, Wu et al. identified a correlation between obesity and a higher rate of residual disease post-treatment and a shorter time-to-progression in their retrospective analysis.
      • Wu S.E.
      • Charles H.W.
      • Park J.S.
      • Goldenberg A.S.
      • Deipolyi A.R.
      Obesity conveys poor outcome in patients with hepatocellular carcinoma treated by transarterial chemoembolization.
      However, both studies were conducted with a limited number of patients. Thus, currently no clear recommendation on the use of TACE in NAFLD-HCC can be made.

      Selective internal radiation therapy

      Evidence on selective internal radiation therapy (SIRT) in patients with NAFLD-HCC is limited. In a retrospective single-centre study, Schotten et al. investigated the impact of NAFLD-related comorbidities on the safety and efficacy of SIRT.
      • Schotten C.
      • Bechmann L.P.
      • Manka P.
      • Theysohn J.
      • Dechêne A.
      • El Fouly A.
      • et al.
      NAFLD-associated comorbidities in advanced stage HCC do not alter the safety and efficacy of yttrium-90 radioembolization.
      Compared to the control group of patients with HBV-related HCC, no significant differences in survival were observed. Additionally, SIRT-related toxicity did not differ between either group. NAFLD-related comorbidities did not influence the safety of the procedure or the oncologic outcome. Thus, the authors concluded that SIRT is a safe and effective treatment option for patients with NAFLD-HCC.
      • Schotten C.
      • Bechmann L.P.
      • Manka P.
      • Theysohn J.
      • Dechêne A.
      • El Fouly A.
      • et al.
      NAFLD-associated comorbidities in advanced stage HCC do not alter the safety and efficacy of yttrium-90 radioembolization.
      Following this first evidence, SIRT might be a treatment option for locally advanced HCC when systemic treatment is limited due to the NAFLD-associated metabolic syndrome and its complications.

      Systemic therapy

      Patients with advanced-stage HCC (BCLC C), preserved hepatic function (Child-Pugh A and B) and an ECOG performance status between 0-2 are candidates for systemic therapy.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Llovet J.M.
      • Kelley R.K.
      • Villanueva A.
      • Singal A.G.
      • Pikarsky E.
      • Roayaie S.
      • et al.
      Hepatocellular carcinoma.
      Additionally, systemic therapy is recommended for patients whose cancers are not amenable to LRTs or after tumour progression upon LRT.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      The efficacy and safety of systemic therapy for the subgroup of patients with NAFLD-HCC is largely unknown (summarised in Table 2).
      In advanced HCC, there have been signals that immune checkpoint inhibitors may be less effective in NAFLD-HCC compared with viral HCC, but this requires validation. As of today, the influence of aetiology on the response to the currently approved treatments is unclear.
      Table 2Overview of outcomes of patients with viral and non-viral HCC in phase III trials of approved systemic agents.
      TrialAetiologyTreatment arm (n)nControl arm (n)nMedian OS, monthsMedian OS depending on aetiology, monthsHR (95% CI) for OS depending on aetiology
      SHARP
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.-F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Bruix J.
      • Raoul J.-L.
      • Sherman M.
      • Mazzaferro V.
      • Bolondi L.
      • Craxi A.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
      ViralSorafenib (299)118Placebo (303)10910.7 vs. 7.9HBV: 9.7 vs. 6.1; HCV: 14.0 vs. 7.4HBV: 0.76 (0.38–1.50); HCV: 0.50 (0.32–0.77)
      Non-viral181194n.a.n.a.
      NAFLD/NASHn.a.n.a.n.a.n.a.
      REFLECT
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.-H.
      • Ikeda K.
      • Piscaglia F.
      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      ViralLenvatinib (478)362Sorafenib (476)37913.6 vs. 12.3HBV: 13.4 vs. 10.2; HCV: 15.3 vs. 14.1HBV: 0.83 (0.68–1.02); HCV: 0.91 (0.66–1.26)
      Non-viral11697n.a.n.a.
      NAFLD/NASHn.a.n.a.n.a.n.a.
      RESORCE
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • Bodoky G.
      • et al.
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ViralRegorafenib (379)221Placebo (194)11410.6 vs. 7.8n.a.HBV: 0.58 (0.41–0.82); HCV: 0.79 (0.49–1.26)
      Non-viral15880n.a.
      NAFLD/NASH2513n.a.
      CELESTIAL
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
      ViralCabozantinib (470)283Placebo (237)14010.2 vs. 8.0n.a.HBV
      HBV with or without HCV.
      : 0.69 (0.51–0.94); HCV
      HCV without HBV.
      : 1.11 (0.72–1.71)
      Non-viral187970.72 (0.54–0.96)
      NAFLD/NASH4323n.a.
      REACH-2
      • Zhu A.X.
      • Kang Y.-K.
      • Yen C.-J.
      • Finn R.S.
      • Galle P.R.
      • Llovet J.M.
      • et al.
      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.
      ViralRamucirumab (197)114Placebo (95)608.5 vs. 7.3n.a.HBV: 0.84 (0.52–1.35); HCV: 0.76 (0.44–1.33)
      Non-viral74240.63 (0.38–1.06)
      NAFLD/NASH194n.a.
      CheckMate 459
      • Yau T.
      • Park J.W.
      • Finn R.S.
      • Cheng A.-L.
      • Mathurin P.
      • Edeline J.
      • et al.
      CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC).
      ViralNivolumab (371)n.a.Sorafenib (372)n.a.16.4 vs. 14.7n.a.n.a.
      Non-viraln.a.n.a.
      NAFLD/NASHn.a.n.a.
      Keynote 240
      • Finn R.S.
      • Ryoo B.-Y.
      • Merle P.
      • Kudo M.
      • Bouattour M.
      • Lim H.Y.
      • et al.
      Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial.
      ViralPembrolizumab (278)115Placebo (135)5013.9 vs. 10.6n.a.HBV: 0.57 (0.35–0.94); HCV: 0.96 (0.48–1.92)
      Non-viral163850.88 (0.64–1.20)
      NAFLD/NASHn.a.n.a.n.a.
      IMbrave150
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
      ViralAtezolizumab + Bevacizumab (336)236Sorafenib (165)11219.2 vs. 13.4HBV: 19.0 vs. 12.4; HCV: 24.6 vs. 12.6HBV: 0.58 (0.40–0.83); HCV: 0.43 (0.25–0.73)
      Non-viral1005317.0 vs. 18.11.05 (0.68–1.63)
      NAFLD/NASHn.a.n.a.n.a.n.a.
      HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OS, overall survival.
      HBV with or without HCV.
      †† HCV without HBV.
      Until 2007, no systemic therapy was available for advanced HCC, demonstrating its distinct resistance to classical chemotherapeutic agents.
      • Marin J.J.G.
      • Macias R.I.R.
      • Monte M.J.
      • Romero M.R.
      • Asensio M.
      • Sanchez-Martin A.
      • et al.
      Molecular bases of drug resistance in hepatocellular carcinoma.
      The SHARP phase III trial established the oral multikinase inhibitor sorafenib as the first-line systemic therapy for advanced-stage HCC for more than a decade.
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.-F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      A subgroup analysis of the SHARP trial showed that the efficacy of sorafenib may depend on the underlying aetiology of HCC.
      • Bruix J.
      • Raoul J.-L.
      • Sherman M.
      • Mazzaferro V.
      • Bolondi L.
      • Craxi A.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
      In detail, patients with non-HCV-associated HCC benefited less from a systemic therapy with sorafenib.
      • Bruix J.
      • Cheng A.-L.
      • Meinhardt G.
      • Nakajima K.
      • Sanctis Y de
      • Llovet J.
      Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies.
      However, only viral HCC vs. alcohol-driven HCC was compared in this analysis.
      • Bruix J.
      • Raoul J.-L.
      • Sherman M.
      • Mazzaferro V.
      • Bolondi L.
      • Craxi A.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
      Recently, Kolamunnage-Dona et al. found that sorafenib’s effect is superior in HCV-seropositive patients who exhibited significantly slower tumour growth and alpha-fetoprotein increases.
      • Kolamunnage-Dona R.
      • Berhane S.
      • Potts H.
      • Williams E.H.
      • Tanner J.
      • Janowitz T.
      • et al.
      Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma.
      Given that sorafenib does not influence HCV RNA levels,
      • El Dika I.H.
      • Geyer S.M.
      • Nixon A.B.
      • Innocenti F.
      • Shi Q.
      • Jacobson S.B.
      • et al.
      Alliance/CALGB 80802: impact of hepatitis C (HCV) on doxorubicin (DO) + sorafenib (S) versus S in patients (pts) with advanced hepatocellular carcinoma (aHCC).
      this finding has to be mediated by a direct effect of sorafenib on malignant cells and/or the tumour immune microenvironment. A recent cohort study comprising 5,201 patients found that the efficacy and safety of sorafenib was similar in NAFLD-HCC compared to other underlying aetiologies.
      • Howell J.
      • Samani A.
      • Mannan B.
      • Hajiev S.
      • Aval L.M.
      • Abdelmalak R.
      • et al.
      Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study.
      However, only 3.6% of this cohort had NAFLD-HCC. Thus, these data should be considered susceptible to bias.
      Remarkably, patients with HCC and type II diabetes treated with metformin had a significantly worse outcome on systemic therapy with sorafenib than patients without type II diabetes, whereas the use of insulin prolonged survival.
      • Casadei Gardini A.
      • Faloppi L.
      • Matteis S de
      • Foschi F.G.
      • Silvestris N.
      • Tovoli F.
      • et al.
      Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: validation study and biological rationale.
      In recent years, immunotherapy has emerged as a new mainstay of systemic oncological treatment for unresectable HCC. However, evidence is mounting that the underlying aetiology that drives hepatocarcinogenesis may influence the efficacy of immune-based therapeutic approaches.
      • Roderburg C.
      • Wree A.
      • Demir M.
      • Schmelzle M.
      • Tacke F.
      The role of the innate immune system in the development and treatment of hepatocellular carcinoma.
      This is particularly relevant for NAFLD-HCC as it more frequently diagnosed at an advanced stage when systemic therapy plays a key role. Thus, biomarkers that can predict response to immunotherapy are a major unmet need.
      The IMbrave150 phase III trial established the combination of atezolizumab with the anti-vascular endothelial growth factor (VEGF)-A antibody bevacizumab as new first-line standard-of-care for patients without prior systemic therapy.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Atezolizumab/bevacizumab improved median OS by 5.8 months and progression-free survival (PFS) by 2.6 months compared to sorafenib, with comparable rates of adverse events among the 2 groups. However, 69.5% of the study population had viral HCC. A recent updated subgroup analysis of the IMbrave150 trial reported that atezolizumab/bevacizumab yielded no OS benefit compared to sorafenib for patients with non-viral HCC (median OS 17.0 months vs. 18.1 months).
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
      The KEYNOTE-240 phase III trial showed no improvement regarding OS and PFS of pembrolizumab in patients with prior sorafenib therapy.
      • Finn R.S.
      • Ryoo B.-Y.
      • Merle P.
      • Kudo M.
      • Bouattour M.
      • Lim H.Y.
      • et al.
      Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial.
      Importantly, the KEYNOTE-240 study cohort comprised a majority of non-viral HCC (60.0%). Likewise, the CheckMate-459 phase III trial failed to show a significantly longer OS or PFS with nivolumab vs. sorafenib as first-line therapy.
      • Yau T.
      • Park J.W.
      • Finn R.S.
      • Cheng A.-L.
      • Mathurin P.
      • Edeline J.
      • et al.
      CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC).
      Furthermore, patients with non-viral HCC benefited less from nivolumab.
      • Pinter M.
      • Scheiner B.
      • Peck-Radosavljevic M.
      Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups.
      A recent meta-analysis of these 3 phase III trials comprising a total of 1,656 patients with unresectable HCC found that immunotherapy improved OS in patients with viral HCC but not in patients with non-viral HCC.
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      Although differentiation of aetiologies in the non-viral group was lacking, these results suggest that patients with NAFLD-HCC seem to benefit less from immune-based therapeutic approaches. Furthermore, the same study showed in 2 cohorts of 130 and 118 patients, respectively, that anti-PD1/PD-L1-based immunotherapy was linked to a reduced median OS in patients with NAFLD-HCC,
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      which is in line with the updated OS data from the IMbrave150 trial.
      Recently, a meta-analysis of 8 randomised controlled trials comprising 3,739 patients confirmed that therapy with ICIs is less efficacious in patients with non-viral HCC.
      • Haber P.K.
      • Puigvehí M.
      • Castet F.
      • Lourdusamy V.
      • Montal R.
      • Tabrizian P.
      • et al.
      Evidence-based management of HCC: Systematic review and meta-analysis of randomized controlled trials (2002-2020).
      In contrast, the efficacy of tyrosine kinase inhibitor- or anti-VEGF-based therapies was not significantly influenced by the underlying aetiology of HCC.
      • Haber P.K.
      • Puigvehí M.
      • Castet F.
      • Lourdusamy V.
      • Montal R.
      • Tabrizian P.
      • et al.
      Evidence-based management of HCC: Systematic review and meta-analysis of randomized controlled trials (2002-2020).
      In vivo studies found that anti-PD1/PD-L1 immunotherapy did not lead to tumour regression in mice with NAFLD-driven HCC.
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      CD8+PD1+ T cells seem to promote tumourigenesis in vivo and human NASH liver tissue shows an equally high number of activated CD8+PD1+ T cells. Interestingly, prophylactic anti-PD1 administration enhanced HCC incidence in NASH mice.
      • Pfister D.
      • Núñez N.G.
      • Pinyol R.
      • Govaere O.
      • Pinter M.
      • Szydlowska M.
      • et al.
      NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
      In contrast, immune checkpoint inhibition prevented hepatocarcinogenesis in a non-NASH mouse model.
      • Chung A.S.
      • Mettlen M.
      • Ganguly D.
      • Lu T.
      • Wang T.
      • Brekken R.A.
      • et al.
      Immune checkpoint inhibition is safe and effective for liver cancer prevention in a mouse model of hepatocellular carcinoma.
      Furthermore, methionine-choline-deficient diet-induced NASH impaired the efficacy of immunotherapy against intrahepatic melanoma metastases in vivo by selectively decreasing CD4+ T cells and creating a more immunosuppressive tumour immune microenvironment.
      • Heinrich B.
      • Brown Z.J.
      • Mathias V.
      • Fu Q.
      • Ma C.
      • Yu S.J.
      • et al.
      Abstract 1728: nonalcoholic steatohepatitis (NASH) impairs treatment of intrahepatic metastases with CD4 + T cell dependent RNA vaccine.
      Taken together, these findings argue for a decreased efficacy of immunotherapy in NAFLD-HCC.
      In addition, obesity may impair the efficacy of anti-angiogenic treatment with bevacizumab.
      • Pinter M.
      • Scheiner B.
      • Peck-Radosavljevic M.
      Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups.
      Importantly, VEGF levels and BMI are positively correlated and more than 50% of individuals with NAFLD are obese.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Loebig M.
      • Klement J.
      • Schmoller A.
      • Betz S.
      • Heuck N.
      • Schweiger U.
      • et al.
      Evidence for a relationship between VEGF and BMI independent of insulin sensitivity by glucose clamp procedure in a homogenous group healthy young men.
      Increased visceral fat area and BMI levels >30 kg/m2 were associated with a decreased OS in patients with metastatic colorectal cancer treated with bevacizumab-based regimens, respectively.
      • Guiu B.
      • Petit J.M.
      • Bonnetain F.
      • Ladoire S.
      • Guiu S.
      • Cercueil J.-P.
      • et al.
      Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer.
      ,
      • Artaç M.
      • Korkmaz L.
      • Coşkun H.Ş.
      • Dane F.
      • Karabulut B.
      • Karaağaç M.
      • et al.
      Bevacuzimab may Be less effective in obese metastatic colorectal cancer patients.
      Correspondingly, elevated BMI levels correlated with extended OS in patients with advanced colorectal cancer treated with standard chemotherapy but not in patients receiving chemotherapy plus bevacizumab.
      • Simkens L.H.J.
      • Koopman M.
      • Mol L.
      • Veldhuis G.J.
      • Bokkel Huinink D ten
      • Muller E.W.
      • et al.
      Influence of body mass index on outcome in advanced colorectal cancer patients receiving chemotherapy with or without targeted therapy.
      However, a subgroup analysis of 8 first-line metastatic colorectal cancer trials comprising 2,118 patients did not show significant differences in OS or PFS after treatment with or without bevacizumab.
      • Aparicio T.
      • Ducreux M.
      • Faroux R.
      • Barbier E.
      • Manfredi S.
      • Lecomte T.
      • et al.
      Overweight is associated to a better prognosis in metastatic colorectal cancer: a pooled analysis of FFCD trials.
      In contrast, obesity was associated with extended survival in patients with non-small cell lung cancer undergoing systemic therapy with ICIs.
      • Khaddour K.
      • Gomez-Perez S.L.
      • Jain N.
      • Patel J.D.
      • Boumber Y.
      Obesity, sarcopenia, and outcomes in non-small cell lung cancer patients treated with immune checkpoint inhibitors and tyrosine kinase inhibitors.
      In particular, elevated BMI levels were independently associated with prolonged OS in patients with non-small cell lung cancer on therapy with atezolizumab.
      • Kichenadasse G.
      • Miners J.O.
      • Mangoni A.A.
      • Rowland A.
      • Hopkins A.M.
      • Sorich M.J.
      Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer.
      A recent retrospective multicentre study of 976 patients with non-small cell lung cancer, melanoma, renal cell carcinoma and other tumour entities (2.4%), treated with anti-PD1/PD-L1 inhibitors, demonstrated a significantly improved PFS and OS for obese individuals.
      • Cortellini A.
      • Bersanelli M.
      • Buti S.
      • Cannita K.
      • Santini D.
      • Perrone F.
      • et al.
      A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable.
      Thus, overweight/obesity appears to be a protective factor for patients undergoing therapy with ICIs.
      Given that patients with NAFLD-HCC are older on average than those with non-NAFLD-HCC, the impact of age on the efficacy of immunotherapy is of great interest. A meta-analysis by Landre et al., including 15 phase III trials with a total of 906 patients ≥75 years-old, confirmed the efficacy of ICIs in this patient cohort, at least in the first-line setting.
      • Landre T.
      • Des Guetz G.
      • Chouahnia K.
      • Fossey-Diaz V.
      • Culine S.
      Immune checkpoint inhibitors for patients aged ≥ 75 Years with advanced cancer in first- and second-line settings: a meta-analysis.
      Accordingly, another recent meta-analysis, comprising 24 randomised trials, found no significant differences regarding the outcome of patients on ICI therapy in different age groups.
      • Ninomiya K.
      • Oze I.
      • Kato Y.
      • Kubo T.
      • Ichihara E.
      • Rai K.
      • et al.
      Influence of age on the efficacy of immune checkpoint inhibitors in advanced cancers: a systematic review and meta-analysis.
      The REFLECT phase III trial confirmed the non-inferiority of the multikinase inhibitor lenvatinib compared to sorafenib in previously untreated HCC. However, only 21% of patients suffered from a non-viral/non-alcohol-associated liver disease.
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.-H.
      • Ikeda K.
      • Piscaglia F.
      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      Remarkably, a recent retrospective study found similar OS rates and even an extended PFS by 1.5 months for lenvatinib in NAFLD-HCC vs. viral- and alcohol-related HCC.
      • Hiraoka A.
      • Kumada T.
      • Tada T.
      • Tani J.
      • Kariyama K.
      • Fukunishi S.
      • et al.
      Efficacy of Lenvatinib for Unresectable Hepatocellular Carcinoma Based on Background Liver Disease Etiology.
      Three phase III trials (RESORCE, CELESTIAL, REACH-2) established regorafenib (a multi-kinase inhibitor against VEGFR1-3),
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • Bodoky G.
      • et al.
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      cabozantinib (a multi-kinase inhibitor against VEGFR1-3, MET and AXL)
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
      and ramucirumab (a VEGFR2 antibody)
      • Zhu A.X.
      • Kang Y.-K.
      • Yen C.-J.
      • Finn R.S.
      • Galle P.R.
      • Llovet J.M.
      • et al.
      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.
      as second-line treatment after tumour progression on sorafenib. However, only 6.6% (RESORCE), 9.3% (CELESTIAL) and 7.9% (REACH-2) of patients included in these studies had NAFLD-HCC, reflecting the low incidence of this aetiology.
      More research is needed to clarify the role of aetiology in NAFLD-HCC and to optimise the management of patients affected by this condition.
      In summary, given the currently available data, it is impossible to draw conclusions regarding the efficacy of the currently approved systemic agents for different HCC aetiologies. However, in the absence of any signals suggesting otherwise they can be considered equally safe across viral and non-viral aetiologies.

      Outlook and future directions

      The management of HCC continues to pose significant clinical challenges, and many open issues remain to be addressed by the scientific community. In principle, those which apply to HCC in general, also apply to NAFLD-HCC in particular. However, there are certain challenges and issues which are unique to NAFLD-HCC (summarised in Table 3). Potentially the most important aspect is prevention: To prevent NAFLD and NASH in the first place (primary prevention), and to prevent the occurrence of HCC in NAFLD/NASH-affected livers (secondary prevention). The former is obviously the best strategy for mitigating the anticipated burden of NAFLD-HCC in the coming decades. The latter may become an emerging topic in the coming years as the first drugs for the treatment of NAFLD and NASH pass the bar of regulatory approval. Indeed, the efficacy of a given drug in terms of secondary prevention may become an important differentiating factor once more agents have become available for routine clinical use. Furthermore, secondary prevention may turn out to be an unexpected but welcome relief for healthcare systems strained by demographic change, obesity, and complications of metabolic disease such as NAFLD and NASH.
      Table 3Overview of current clinical challenges and open issues regarding the management of patients with NAFLD-HCC.
      Clinical setting/treatmentClinical challengesOpen issues
      PreventionReducing the number of patients who develop NAFLD/NASH and subsequently HCC
      • Developing effective treatments for NAFLD/NASH which reduce the risk of HCC
      • Developing treatments which reduce the risk of HCC in patients with NAFLD/NASH
      SurveillanceDetecting HCC in patients with NAFLD-HCC as early as possible in order to maximize the odds of a cure
      • Identifying patients with NAFLD-HCC but without cirrhosis who are at risk of developing HCC and in who surveillance is cost effective
      • Developing surveillance strategies with higher sensitivity and specificity than abdominal ultrasound
      Liver resectionReducing postoperative morbidity and mortality and increasing recurrence-free survival of patients with NAFLD-HCC
      • Optimising the surgical method to reduce the risk of postoperative complications and recurrence
      Liver transplantationIncreasing the number of patients with NAFLD-HCC who receive a liver transplant
      • Identifying patients with NAFLD-HCC who do not meet the current transplantation criteria but who have a low risk of HCC recurrence and would therefore be suitable candidates for a liver transplant
      Locoregional treatmentImproving the outcome of patients with NAFLD-HCC after locoregional treatments
      • Improving the efficacy of available locoregional treatments
      • Improving patient selection for locoregional vs. systemic treatment
      • Identifying the right time-point to transition patients with NAFLD-HCC from locoregional to systemic treatments
      Adjuvant treatmentIncreasing recurrence-free and overall survival of patients with NAFLD-HCC
      • Developing a medical treatment which reduces the risk of recurrence in patients with NAFLD-HCC
      Systemic treatmentIncreasing progression-free and overall survival of patients with NAFLD-HCC
      • Identifying patients who respond to ICI-containing regimens vs. those who do not
      • Developing novel, more effective systemic agents
      HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.
      Another important aspect is surveillance. Detecting NAFLD-HCC at earlier stages would enable more patients to undergo curative treatment, improving the overall prognosis of this subgroup. However, a couple of important issues need to be resolved: i) defining the subgroup of patients who are at risk and in whom a surveillance programme would be cost effective. It is clear that patients with cirrhosis need to undergo surveillance, but it needs to be clarified which patients with NAFLD or NASH without cirrhosis would also benefit from surveillance. ii) developing surveillance strategies with higher sensitivity and specificity than abdominal ultrasound. Ultrasound is obviously the central tool in current surveillance programmes, but it suffers from methodological constraints, which become particularly apparent in obese patients. Therefore, optimised surveillance strategies involving contrast-enhanced cross-sectional imaging need to be established for patients with NAFLD/NASH.
      In terms of treatment, the overarching goal of all available modalities is to become more effective while providing a high degree of safety. While each modality may have room for improvement, the outcome of patients with NAFLD-HCC may also be improved by adapting the current treatment algorithm to the distinctive features of this subgroup. For example, transplantation criteria could be extended to include patients with NAFLD-HCC and a low risk of recurrence despite exceeding the current set of criteria. Furthermore, the development of predictive biomarkers could guide treatment selection, especially with regard to locoregional and systemic treatments. This would help to control overutilisation of ineffective treatments and reduce unnecessary costs as well as side effects. In particular, patients should be transitioned from locoregional to systemic treatment when the former has failed. Moreover, the benefit of one class of systemic agents over another in patients with NAFLD-HCC or a subgroup thereof needs to be established.
      In total, these clinical challenges and open issues provide ample opportunity for basic and clinical HCC researchers to contribute to the continuous improvement in the management of patients with NAFLD-HCC. Ongoing clinical trials give reason to be optimistic that several of the mentioned issues will be addressed in the near future.

      Conclusion

      As a consequence of the NASH pandemic, NAFLD-HCC is undoubtedly a growing global healthcare issue. Since it has been of relatively small relevance so far, many open questions remain regarding its management and particularly its treatment. What is generally accepted is that NAFLD-HCC occurs in non-cirrhotic livers more frequently than non-NAFLD-HCC. Furthermore, it tends to be more advanced at diagnosis. This has a notable effect on the treatment of patients with NAFLD-HCC: they undergo hepatic resection more and liver transplantation less frequently. However, beyond that, today’s treatment algorithms do not consider the aetiology of HCC. Therefore, data on the safety and efficacy of locoregional and systemic treatments in NAFLD-HCC are scarce. Importantly, NAFLD/NASH accounts for only a small proportion of underlying aetiologies in most studies, whereas the "unknown" category usually includes significantly more patients. Therefore, it must be assumed that NAFLD/NASH is underdiagnosed. As there is increasing evidence that the underlying aetiology plays an important role in the response to specific therapies, this should be considered in future studies. Overall, the established treatments appear to be as safe in NAFLD-HCC as in non-NAFLD-HCC. Post hoc analyses of the pivotal phase III studies have provided hints that a given treatment may work better in one aetiology than in another. Recently, the case has been made that ICIs are less efficacious in NAFLD-HCC than in viral HCC. However, the available evidence is hypothesis generating but insufficient to draw a definitive conclusion, since post hoc subgroup analyses are prone to bias. As is true for many open questions regarding the management of HCC subgroups, randomised controlled trials are needed to clarify which treatment works best for the different aetiologies of HCC. In addition, future registrational clinical trials are well advised to use HCC aetiology (viral vs. non-viral) as a stratification factor. However, molecular heterogeneity within a given aetiological group will continue to hamper patient stratification. One potential solution is biomarker-based therapeutic algorithms which have yet to be translated into the clinic, but which hold promise for substantially improving clinical decision making. With the NASH pandemic having no end in sight, identifying the optimal treatment for patients with NAFLD-HCC will keep clinicians and scientists occupied for the foreseeable future.

      Abbreviations

      BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitors; LT, liver transplantation; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OS, overall survival; PD1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; RFA, radiofrequency ablation; RFS, recurrence-free survival; SBRT, stereotactic body radiation therapy; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolisation; TTP, time to progression; VEGF, vascular endothelial growth factor.

      Financial support

      SJG and LM are supported by the Clinician Scientist Fellowship “Else Kröner Research College: 2018_Kolleg.05”. Otherwise, this work was not financially supported by any grant or funding source.

      Authors’ contributions

      All of the authors performed the research, writing, and review of all of the drafts of this paper and approved the final version.

      Conflict of interest

      FF reports receiving consulting and lectures fees from Roche; lectures fees from Lilly and Pfizer. SJG and LM report no conflict of interest. PRG reports receiving consulting and lectures fees from Adaptimmune, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, Roche, Sirtex.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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