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Systemic treatment of HCC in special populations

  • Lorenza Rimassa
    Correspondence
    Corresponding author. Address: Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy. Tel.: 39 02 82244573; fax: 39 02 82244590.
    Affiliations
    Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, 20089 Rozzano (Milan), Italy

    Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
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  • Nicola Personeni
    Affiliations
    Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Via Manzoni 56, 20089 Rozzano (Milan), Italy

    Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
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  • Carolin Czauderna
    Affiliations
    Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany

    Department of Medicine I, University Medical Center Schleswig-Holstein – Campus, Lübeck, Germany
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  • Friedrich Foerster
    Affiliations
    Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany
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  • Peter Galle
    Affiliations
    Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Germany
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Published:November 25, 2020DOI:https://doi.org/10.1016/j.jhep.2020.11.026

      Summary

      Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.

      Keywords

      Introduction

      Since 2007, the multikinase inhibitor (MKI) sorafenib has been the global standard of care for patients with hepatocellular carcinoma (HCC), preserved liver function and advanced or intermediate stage disease not suitable for locoregional treatments.
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      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      After a decade of unsatisfactory results, additional agents with prevalent antiangiogenic properties have been approved either as first-line alternatives to sorafenib,
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      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      or in a second-line setting, after sorafenib.
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      • Granito A.
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      • et al.
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
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      • et al.
      Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
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      • et al.
      Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Also, immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD-1) receptor have recently been granted accelerated approval.
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      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      ,
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      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      Although trials testing ICIs alone have failed to meet their respective primary endpoints,
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      • 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.
      ,
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      • Cheng A.
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      • Edeline J.
      • Kudo M.
      • et al.
      LBA38_PR: CheckMate 459: a randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC).
      novel combinations of ICIs plus agents that target angiogenesis have shown promise in treatment-naïve patients.
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      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Moreover, strategies combining a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody plus an anti-PD-1 antibody have been approved in patients previously treated with sorafenib.
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      Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (PTS) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.
      Despite the unprecedented wealth of systemic treatment options now available,
      • Personeni N.
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      • Rimassa L.
      Which choice of therapy when many are available? Current systemic therapies for advanced hepatocellular carcinoma.
      there exist special populations for whom, paradoxically, no treatment can be recommended because of a lack of clinical information for their specific conditions. Historically, these patients represent an unmet medical need.
      HCC clinical trials usually exclude individuals with HIV, a history of solid organ transplantation, decompensated cirrhosis, or fibrolamellar HCC (FLHCC). Similarly, active autoimmune diseases are typical exclusion criteria for virtually all clinical trials involving ICIs. In contrast, evidence on the treatment of patients with portal vein thrombosis (PVT) is more heterogeneous, since some trials considered it an exclusion criterion, while others did not (Table 1). Despite the lack of an upper age limit, elderly patients are often underrepresented in clinical trials
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      Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations.
      and, therefore, more data are required to properly inform treatment decisions. Due to the lack of applicable, high-quality evidence from prospective clinical trials, there exist some medical conditions, such as bleeding, metabolic syndrome and concurrent haemodialysis, that pose concrete challenges in daily practice (Table 2).
      Phase III trials of systemic agents for HCC excluded patients with relevant and frequent comorbidities.
      Table 1Inclusion and exclusion of special populations of HCC patients in phase III trials.
      Special populationSHARP
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      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.
      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.
      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.
      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.
      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 alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      CheckMate 459
      • Yau T.P.J.
      • Finn R.S.
      • Cheng A.
      • Mathurin P.
      • Edeline J.
      • Kudo M.
      • et al.
      LBA38_PR: CheckMate 459: a randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC).
      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.
      Solid organ transplantationNONONONONONONONO
      HIVNONONONONONONONO
      Prior or active autoimmune diseasesYESYESNOYESYESYESNONO
      Significant cardiovascular diseaseNONONONONONONOYES
      Diabetes/metabolic syndromeYESYESYESYESYESYESYESYES
      Fibrolamellar, mixed HCC/CCC, other histological subtypesNONONONONONONONO
      Decompensated cirrhosis (Child-Pugh B and C)YES
      Child-Pugh C excluded.
      NONONONONONONO
      Elderly patientsYESYESYESYESYESYESYESYES
      Significant bleeding historyNONONONONONONONO
      HaemodialysisNONONONONONONONO
      Vascular invasion/portal vein thrombosisYESYES
      Vp4 excluded.
      YESYESYESYESYESYES
      Vp4 excluded.
      NO means patients are excluded; YES means patients are included.
      HCC/CCC, mixed hepatocellular/cholangiocellular carcinoma.
      Child-Pugh C excluded.
      ∗∗ Vp4 excluded.
      Table 2Factors and open issues to consider in the management of special populations of HCC patients.
      Special populationImpact on prognosisContraindicated treatmentsClinical challengesOpen issues
      Solid organ transplantationPositiveCheckpoint inhibitorsInfectionsHow to safely apply immunotherapy without increasing the risk of graft rejection
      HIVNegativeNo data available
      Available data for sorafenib and regorafenib confirm the safety profile of the two drugs; no data available for other agents.
      Drug-drug interaction (cART)Elucidate biological underpinnings of aggressive disease,

      Multidisciplinary and worldwide collaboration to characterise biology, treatment, and survivorship,

      Increase clinical trial accrual,

      Clarify optimal treatment strategies
      Prior or active autoimmune diseasesNoneCheckpoint inhibitors to be used with cautionFlare managementSafe use of checkpoint inhibitors
      Significant cardiovascular diseasePotentially negativeAntiangiogenicsCardiovascular events, thromboembolic eventsAnticipate life expectancy, Clarify optimal treatment strategies
      Diabetes/metabolic syndromePotentially negativeBevacizumab, ramucirumab and lenvatinib to be used with caution in case of proteinuriaObesity, diabetic/metabolic complicationsExplore the potential of anti-inflammatory/-fibrotic treatments to reduce the risk of HCC,

      Validate the potentially protective effect of metformin
      Fibrolamellar, mixed HCC/CCC, other histological subtypesNegativeNoneLack of trial data to support clinical decision-makingDiscover targeted treatments (e.g., using basket or umbrella trials),

      Explore benefit of immuno- and combination therapies
      Decompensated cirrhosis (Child- Pugh B and C)NegativeAny systemic treatment in Child-Pugh CAscites, HRS, ACLF, wastingIdentify patients who benefit from systemic therapy despite impaired liver function,

      Define safe and effective treatment protocols
      Elderly patientsNoneNoneComorbidities, drug-drug interactions, complianceIncrease clinical trial accrual,

      Geriatric assessment of frailty,

      Predict, prevent, and mitigate toxicity
      Significant bleeding historyNegativeAntiangiogenics (based on current risk)Repeated bleeding events despite screening/treatment of varicesMultidisciplinary collaboration to define optimal management of varices,

      Anticipate life expectancy
      HaemodialysisPotentially negativeNo data available
      Available data for sorafenib confirm the safety profile of the drug; no data available for other agents.
      Impaired drug metabolism and risk of higher plasma concentrationAddress dosing, toxicity, and life expectancy, Multidisciplinary and worldwide collaboration
      Vascular Invasion/portal vein thrombosisNegativeNonePortal hypertension, oesophageal varicesDefine most effective treatment strategies
      ACLF, acute-on-chronic liver failure; cART, combined antiretroviral therapy; HCC/CCC, mixed hepatocellular/cholangiocellular carcinoma; HRS, hepatorenal syndrome.
      Available data for sorafenib and regorafenib confirm the safety profile of the two drugs; no data available for other agents.
      ∗∗ Available data for sorafenib confirm the safety profile of the drug; no data available for other agents.
      As there is a clear need to adhere to real-world scenarios, our review paper summarises current knowledge regarding approved treatments in these special populations, highlighting challenges and potential future directions.

      Patients after solid organ transplantation

      Solid organ transplant recipients carry a higher risk of de novo malignancies, which affect long-term survival.
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      Clinical significance of de novo malignancy after liver transplant: a single-center study.
      In western cohorts, the incidence of HCC in non-liver graft recipients was similar to that in the general population, while it was elevated among liver graft recipients.
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      • Subramanian A.K.
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      Incidence and risk factors for hepatocellular carcinoma after solid organ transplantation.
      ,
      • Koshiol J.
      • Pawlish K.
      • Goodman M.T.
      • McGlynn K.A.
      • Engels E.A.
      Risk of hepatobiliary cancer after solid organ transplant in the United States.
      Despite well-established selection criteria for orthotopic liver transplantation (OLT), HCC recurrence occurs in 10–16% of patients.
      • de'Angelis N.
      • Landi F.
      • Carra M.C.
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      Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review.
      • Mazzaferro V.
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      • Doci R.
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      • Pulvirenti A.
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      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
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      • Weinmann A.
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      Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre.
      While neoadjuvant locoregional therapies prior to transplantation (bridging) are considered to be standard of care, adjuvant therapies post OLT have not demonstrated a significant benefit on HCC recurrence.
      • Zhang Q.
      • Chen H.
      • Li Q.
      • Zang Y.
      • Chen X.
      • Zou W.
      • et al.
      Combination adjuvant chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin after liver transplantation for hepatocellular carcinoma: a preliminary open-label study.
      ,
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      • Broome U.
      • et al.
      A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma.
      Furthermore, immunosuppressive regimens, especially mammalian target of rapamycin (mTOR) inhibitors, have been evaluated for their potential anticancer properties and use in post-OLT management. Small-centre retrospective studies and meta-analyses have reported beneficial effects of mTOR inhibitors, including reduced HCC recurrence rates. However, the largest multicentre randomised controlled trial to date (SILVER study) could not confirm that sirolimus significantly improved recurrence-free survival beyond 5 years.
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      Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.
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      Everolimus and malignancy after solid organ transplantation: a clinical update.
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      Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial.
      Several studies have demonstrated that surgical treatment in well-selected patients with HCC recurrence and limited disease is an independent predictor of long-term survival.
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      • Ahn C.S.
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      Resection of pulmonary metastases from hepatocellular carcinoma following liver transplantation.
      ,
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      • Astete S.
      • Laurence J.M.
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      • Rafael E.
      • et al.
      Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series.
      In case of unresectable HCC recurrence, locoregional and systemic approaches can be applied, but data are limited and restricted to small case series and studies. Data on the safety and efficacy of systemic therapies are mainly based on the use of sorafenib with or without mTOR inhibitors. The safety of sorafenib has been confirmed in the post-transplant setting, wherein it was associated with a median survival of 12 months (1.45–20.1).
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      • Niederle I.M.
      • Koch S.
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      Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.
      ,
      • Mancuso A.
      • Mazzola A.
      • Cabibbo G.
      • Perricone G.
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      • Galvano A.
      • et al.
      Survival of patients treated with sorafenib for hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis.
      Combinations with mTOR inhibitors can lead to increased toxicity, resulting in dose reduction or discontinuation of treatment.
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      • Crocetti L.
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      • Bargellini I.
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      Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.
      ,
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      • Bustamante J.
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      • Salcedo M.
      • Garralda E.
      • Testillano M.
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      Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.
      Therefore, close monitoring is important, especially during the first weeks of treatment. A multicentre retrospective study further showed the safety of regorafenib in the second-line setting in sorafenib-tolerant patients with HCC recurrence after OLT and provided the rationale for sequential therapy.
      • Iavarone M.
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      • Czauderna C.
      • Sanduzzi-Zamparelli M.
      • Bhoori S.
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      • et al.
      Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.
      Experience with ICIs in solid organ transplant recipients is limited because of the increased risk of allograft rejection and graft lost. A retrospective pilot evaluation reported on the safety and efficacy of PD-1 inhibitors in 7 patients with recurrent HCC (n = 5) and melanoma (n = 2) after OLT. Graft rejection was observed in 2 patients with HCC. Only 4 patients were restaged. While 3 patients with HCC recurrence progressed under ICI, 1 patient with metastatic melanoma had a complete response (CR) without graft rejection in this study.
      • DeLeon T.T.
      • Salomao M.A.
      • Aqel B.A.
      • Sonbol M.B.
      • Yokoda R.T.
      • Ali A.H.
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      Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience.
      Further case reports on patients with recurrent HCCs after OLT reported rapid irreversible liver dysfunction under ICI.
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      • Weiler S.
      • Mertens J.C.
      • Reiner C.S.
      • Vrugt B.
      • Nageli M.
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      Liver allograft failure after nivolumab treatment-a case report with systematic literature research.
      ,
      • Friend B.D.
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      • McDiarmid S.V.
      • Zhou X.
      • Naini B.
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      Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.
      Therefore, published data highlight the severe risks of graft loss under immunotherapy, which should not therefore be recommended in the setting of solid organ transplantation (Table 2).

      Patients with HIV

      In people living with HIV (PLWH), due to the high prevalence of coinfection with HBV and HCV, HCC is frequently diagnosed at a young age and at an advanced stage, representing an increasing cause of morbidity and mortality, and accounting for over 40% of liver-related deaths.
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      It is still unclear if HIV may negatively influence the clinical course of HCC or whether PLWH may be safely treated with systemic treatments for HCC.
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      In fact, HIV-positive patients are less likely to receive treatment at recurrence (61% vs. 86.2%, p <0.001)
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      Hepatocellular carcinoma in HIV-infected patients: check early, treat hard.
      and more likely to receive best supportive care for advanced disease (60% vs. 38%, p = 0.02).
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      Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.
      For PLWH with advanced HCC, one concern relates to the potential synergistic toxicity of using systemic treatments alongside combined antiretroviral therapy (cART) (Table 2).
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      Available data are limited and a Spanish real-world study of sorafenib showed a significantly worse outcome compared to historical data on non-HIV-infected patients. However, there were no modifications of cART, and CD4+ T-cell counts, and HIV viral load remained stable.
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      Real-life experience with sorafenib for the treatment of hepatocellular carcinoma in HIV-infected patients.
      In contrast, a retrospective Italian study reported similar efficacy and safety data for sorafenib in PLWHs as in non-HIV patients, with a median OS of 12.8 (range 1.1–23.5) months in PLWHs. Most drug-related adverse events (AEs) were manageable with grade 3–4 diarrhoea, and hand-foot skin reaction (HFSR) in 15% of patients, and hypertension in 11%.
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      Sorafenib for the treatment of unresectable hepatocellular carcinoma in HIV-positive patients.
      The first publication on regorafenib in an HIV-positive patient with advanced HCC reported stable disease, good tolerability, and no impact on the underlying HIV infection.
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      • Julve M.
      • Pinato D.J.
      • Sharma R.
      Regorafenib therapy for hepatocellular carcinoma in a HIV-1-infected patient: a case report.
      The possibility of treating PLWH with advanced HCC with ICIs has been tested in case series and a small phase II study in patients with different cancer types (with a single HCC patient); this study reported similar efficacy and safety data to those achieved in HIV-negative patients, without an impact on HIV viral load or CD4+ T-cell counts.
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      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
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      Nivolumab treatment for cancers in the HIV-infected population.
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      • et al.
      Assessment of the feasibility and safety of Durvalumab for treatment of solid tumors in patients with HIV-1 infection: the phase 2 DURVAST study.
      Given the life expectancy benefits shown by cART and the negative prognostic impact of HCC, there is a compelling need for safe and effective treatments for HCC in PLWH.
      • Dika I.E.
      • Harding J.J.
      • Abou-Alfa G.K.
      Hepatocellular carcinoma in patients with HIV.
      Of note, the ongoing phase IIIb AMETHISTA study of atezolizumab plus bevacizumab as front-line treatment for patients with unresectable HCC (NCT04487067) includes HIV-positive patients provided they are stable on cART, have a CD4+ T-cell count ≥200/μl, and an undetectable viral load. Although this trial is ongoing and no data are yet available, it represents the approach needed to evaluate novel therapies for HCC among PLWH, along with a close collaboration between HCC and HIV specialists (Table 2) since the number of HCC in PLWH is expected to rise.
      • Pinato D.J.
      • Dalla Pria A.
      • Sharma R.
      • Bower M.
      Hepatocellular carcinoma: an evolving challenge in viral hepatitis and HIV coinfection.
      ,
      • Dika I.E.
      • Harding J.J.
      • Abou-Alfa G.K.
      Hepatocellular carcinoma in patients with HIV.

      Patients with prior or active autoimmune diseases

      Autoimmune liver diseases

      It is well established that autoimmune liver disease is a risk factor for HCC.
      • Lleo A.
      • de Boer Y.S.
      • Liberal R.
      • Colombo M.
      The risk of liver cancer in autoimmune liver diseases.
      Regarding autoimmune hepatitis (AIH), a meta-analysis calculated a pooled incidence rate for HCC of 3.06 per 1,000 patient-years.
      • Tansel A.
      • Katz L.H.
      • El-Serag H.B.
      • Thrift A.P.
      • Parepally M.
      • Shakhatreh M.H.
      • et al.
      Incidence and determinants of hepatocellular carcinoma in autoimmune hepatitis: a systematic review and meta-analysis.
      In AIH with cirrhosis at diagnosis, the rate was even higher at 10.07 per 1,000 patient-years. However, the overall risk of HCC seemed to be lower in patients with AIH and cirrhosis compared to patients with cirrhosis related to HBV/HCV infection or primary biliary cholangitis (PBC). A meta-analysis in PBC revealed a significantly higher HCC risk than for the general population, with a pooled risk rate of 18.8.
      • Liang Y.
      • Yang Z.
      • Zhong R.
      Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis.
      High-quality data on the safety and efficacy of currently approved drugs in these patients are missing.
      With only limited data available on the treatment of HCC in the context of autoimmune liver disease there are no apparent restrictions on the use of MKIs and ramucirumab in such patients (Table 2). Yet the safety of ICIs in this group is unclear, since patients with AIH have been excluded from clinical trials with ICI (Table 1). Although ICI-related hepatotoxicity is poorly understood, a pathophysiology similar to AIH has been assumed. However, differences in clinical and pathological features have emerged.
      • Nishida N.
      • Kudo M.
      Liver damage related to immune checkpoint inhibitors.
      Although some authors have suggested that ICIs carry only a small risk of exacerbating preexisting autoimmune disorders and may therefore be used in such patients,
      • Johnson D.B.
      • Sullivan R.J.
      • Menzies A.M.
      Immune checkpoint inhibitors in challenging populations.
      ,
      • Leonardi G.C.
      • Gainor J.F.
      • Altan M.
      • Kravets S.
      • Dahlberg S.E.
      • Gedmintas L.
      • et al.
      Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders.
      there are insufficient data to expand this view to AIH, which warrants evaluation in future clinical trials (Table 2).

      Other autoimmune diseases

      Data regarding the incidence of HCC in patients with non-liver autoimmune disease are missing. Equally, it is unknown which systemic treatments can be used safely and effectively in these patients (Table 1). This is complicated by the large number of different conditions ranging from hypothyroidism with very good prognosis to systemic lupus erythematodes with potentially life-threatening complications. In the absence of contraindications, MKIs and ramucirumab can be employed in these patients (Table 2). However, the situation is less clear for ICIs: some authors have propagated their use in patients with preexisting autoimmune disorders.
      • Johnson D.B.
      • Sullivan R.J.
      • Menzies A.M.
      Immune checkpoint inhibitors in challenging populations.
      ,
      • Leonardi G.C.
      • Gainor J.F.
      • Altan M.
      • Kravets S.
      • Dahlberg S.E.
      • Gedmintas L.
      • et al.
      Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders.
      However, a prospective study of the REISAMIC registry found a significantly increased risk of immune-related AEs (irAEs) in such patients.
      • Danlos F.X.
      • Voisin A.L.
      • Dyevre V.
      • Michot J.M.
      • Routier E.
      • Taillade L.
      • et al.
      Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease.
      A systematic review of 49 studies with a total of 123 patients reported an exacerbation and/or irAE rate of 75%.
      • Abdel-Wahab N.
      • Shah M.
      • Lopez-Olivo M.A.
      • Suarez-Almazor M.E.
      Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review.
      Therefore, ICIs should be used with caution in patients with preexisting autoimmune disease and HCC (Table 2).

      Patients with significant cardiovascular disease

      Due to partly overlapping risk factors, the prevalence of cardiovascular disease (CVD) in the general population, and the incidence in similar age groups, arterial hypertension, coronary heart disease, cerebrovascular disease, and thromboembolic events are frequent comorbidities in patients with HCC.
      • Mu X.M.
      • Wang W.
      • Jiang Y.Y.
      • Feng J.
      Patterns of comorbidity in hepatocellular carcinoma: a network perspective.
      Patients with uncontrolled CVD or recent acute events, such as myocardial infarction, pulmonary embolism or stroke, are excluded from clinical trials assessing systemic treatments for HCC (Table 1). A large cross-sectional Chinese study (n = 22,500) showed that of 2,574 patients with advanced HCC, 25.1% had concomitant hypertension, 4.7% had coronary heart disease, 3% atrial fibrillation, and 2% heart failure. Of note, most patients with HCC had high grade hypertension (76.7%) associated with a higher prevalence of other concomitant CVDs.
      • Liu F.
      • Hidru T.H.
      • Gao R.
      • Lin Y.
      • Liu Y.
      • Fang F.
      • et al.
      Cancer patients with potential eligibility for vascular endothelial growth factor antagonists use have an increased risk for cardiovascular diseases comorbidities.
      Based on these data, although they cannot be extrapolated to other populations, a large number of patients with HCC present with contraindications to antiangiogenic treatment. Moreover, arterial hypertension is a frequently observed treatment-related AE, with an incidence of grade ≥3 arterial hypertension of 15–23%.
      • Rimassa L.
      • Danesi R.
      • Pressiani T.
      • Merle P.
      Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma.
      Conversely, hypertension has been shown to correlate with better outcomes with sorafenib, lenvatinib, and cabozantinib.
      • Rimassa L.
      • Danesi R.
      • Pressiani T.
      • Merle P.
      Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma.
      • Sung M.W.
      • Richard F.
      • Qin S.
      • Han K.-H.
      • Ikeda K.
      • Chen A.-L.
      • et al.
      Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT).
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • Cicin I.
      • Bolondi L.
      • Klu¨mpen H.-J.
      • et al.
      Association of adverse events with efficacy outcomes for cabozantinib in patients with advanced hepatocellular carcinoma in the phase 3 CELESTIAL trial.
      Therefore, blood pressure should be controlled before treatment initiation, should then be monitored regularly, and treated in a timely fashion.
      • Rimassa L.
      • Danesi R.
      • Pressiani T.
      • Merle P.
      Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma.
      Of note, based on their safety profile, ICIs could be considered a potential treatment option for patients with CVD unsuitable for antiangiogenics, but specific data in this patient population are lacking (Table 2).

      Patients with diabetes/metabolic syndrome

      Diabetes and non-alcoholic fatty liver disease (NAFLD) associated with metabolic syndrome have been linked to an increased HCC risk.
      • Schlesinger S.
      • Aleksandrova K.
      • Pischon T.
      • Jenab M.
      • Fedirko V.
      • Trepo E.
      • et al.
      Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.
      The underlying pathophysiology probably involves increased hepatic/peripheral insulin resistance, increased pro-inflammatory mediators, oxidative stress, JNK-1 activation, increased insulin-like growth factor-1 (IGF-1) activity, and an altered gut microbiome.
      • Mantovani A.
      • Targher G.
      Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease.
      Patients with diabetes or metabolic syndrome were not excluded in the registrational trials of the currently approved systemic treatments for HCC (Table 1). Therefore, they can generally be used in patients with these comorbidities without restriction. However, in case of active proteinuria, a frequent diabetic complication, a treatment with bevacizumab, ramucirumab or lenvatinib should be initiated with caution, monitored closely, and discontinued in case of worsening of proteinuria (Table 2).
      There has been some debate regarding whether diabetes treatment affects hepatocarcinogenesis. Recently, a meta-analysis on 8 studies reported a combined odds ratio of 0.468 for the association between HCC and metformin treatment, signalling a potentially protective effect.
      • Cunha V.
      • Cotrim H.P.
      • Rocha R.
      • Carvalho K.
      • Lins-Kusterer L.
      Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review.
      In the HCC treatment setting, mixed signals have been reported: In a meta-analysis of 6 retrospective cohort studies, the use of metformin in patients with type 2 diabetes was associated with a significantly prolonged OS after curative treatment of HCC (p <0.00001).
      • Zhou J.
      • Ke Y.
      • Lei X.
      • Wu T.
      • Li Y.
      • Bao T.
      • et al.
      Meta-analysis: the efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.
      In contrast, a negative effect of metformin in addition to sorafenib has been suggested.
      • Casadei Gardini A.
      • Marisi G.
      • Scarpi E.
      • Scartozzi M.
      • Faloppi L.
      • Silvestris N.
      • et al.
      Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib.
      Future studies on treatments for NAFLD and non-alcoholic steatohepatitis will need to show whether their anti-fibrotic/anti-inflammatory properties translate into protection against HCC (Table 2).

      Patients with fibrolamellar and mixed hepato-cholangiocellular carcinomas

      Despite conventional HCC representing the most common histological type of primary liver cancer, a small subset of patients develop primary hepatic tumours with distinct pathological features, including FLHCC, scirrhous, spindle cell, clear, pleomorphic as well as mixed hepato-cholangiocellular carcinomas (HCC/CCC). Rare subtypes are generally excluded from prospective trials (Table 1) and clinical outcome and treatment approaches are not clearly defined. FLHCC and mixed HCC/CCC represent the most common rare pathological subtypes and will be further discussed.
      • Zakka K.
      • Jiang R.
      • Alese O.B.
      • Shaib W.L.
      • Wu C.
      • Wedd J.P.
      • et al.
      Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma.
      Available evidence stems from low-quality sources, such as case reports, retrospective series and small clinical trials.
      FLHCC occurs more frequently in younger patients (<40 years) without a clear gender preponderance.
      • El Jabbour T.
      • Lagana S.M.
      • Lee H.
      Update on hepatocellular carcinoma: pathologists' review.
      However, 2 peak incidences have been described: one in a younger age group (10–30 years) and one in an elderly age group (70–79 years).
      • Ramai D.
      • Ofosu A.
      • Lai J.K.
      • Gao Z.H.
      • Adler D.G.
      Fibrolamellar hepatocellular carcinoma: a population-based observational study.
      ,
      • Eggert T.
      • McGlynn K.A.
      • Duffy A.
      • Manns M.P.
      • Greten T.F.
      • Altekruse S.F.
      Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000-10.
      Clinically, histologically and molecularly FLHCC is a distinct subtype of HCC. In contrast to conventional HCC, FLHCC has not been associated with risk factors such as viral hepatitis, alcohol or other underlying inflammatory liver diseases.
      • Lin C.C.
      • Yang H.M.
      Fibrolamellar carcinoma: a concise review.
      Besides typical diagnostic features of FLHCC on imaging and histological examinations,
      • Anysz-Grodzicka A.
      • Podgorska J.
      • Cieszanowski A.
      State-of-the-art MR imaging of uncommon hepatocellular tumours: fibrolamellar hepatocellular carcinoma and combined Hepatocellularcholangiocarcinoma.
      a recent study showed DNAJB1-PRKACA fusion mutations to be 100% specific for FLHCC.
      • Honeyman J.N.
      • Simon E.P.
      • Robine N.
      • Chiaroni-Clarke R.
      • Darcy D.G.
      • Lim II,
      • et al.
      Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.
      Clinico-pathological data and survival outcomes are mostly collected from case reports, single-institutional case series and/or registry-based studies.
      • Zakka K.
      • Jiang R.
      • Alese O.B.
      • Shaib W.L.
      • Wu C.
      • Wedd J.P.
      • et al.
      Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma.
      ,
      • Yamashita S.
      • Vauthey J.N.
      • Kaseb A.O.
      • Aloia T.A.
      • Conrad C.
      • Hassan M.M.
      • et al.
      Prognosis of fibrolamellar carcinoma compared to non-cirrhotic conventional hepatocellular carcinoma.
      • Ang C.S.
      • Kelley R.K.
      • Choti M.A.
      • Cosgrove D.P.
      • Chou J.F.
      • Klimstra D.
      • et al.
      Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium.
      • Wahab M.A.
      • El Hanafy E.
      • El Nakeeb A.
      • Ali M.A.
      Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma (experience with 22 patients over a 15-year period).
      • Chakrabarti S.
      • Tella S.H.
      • Kommalapati A.
      • Huffman B.M.
      • Yadav S.
      • Riaz I.B.
      • et al.
      Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
      The treatment of choice is a complete primary resection resulting in 5-year OS rates of 70%. However, recurrence rates are high and (neo)adjuvant therapeutic approaches have not been shown to improve survival.
      • Zakka K.
      • Jiang R.
      • Alese O.B.
      • Shaib W.L.
      • Wu C.
      • Wedd J.P.
      • et al.
      Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma.
      ,
      • Chakrabarti S.
      • Tella S.H.
      • Kommalapati A.
      • Huffman B.M.
      • Yadav S.
      • Riaz I.B.
      • et al.
      Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
      In case of advanced stages of disease, prognosis is poor with a median survival of less than 12 months. Given the rarity of the disease and its limited incidence, no randomised controlled trials have been performed to investigate the most efficacious treatment strategy. Systemic therapies include classical chemotherapies (mainly based on 5-fluorouracil combinations), but FLHCC tends to be chemo-resistant.
      • Chakrabarti S.
      • Tella S.H.
      • Kommalapati A.
      • Huffman B.M.
      • Yadav S.
      • Riaz I.B.
      • et al.
      Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
      Targeted approaches include sorafenib but have shown limited effectiveness.
      • Ang C.S.
      • Kelley R.K.
      • Choti M.A.
      • Cosgrove D.P.
      • Chou J.F.
      • Klimstra D.
      • et al.
      Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium.
      ,
      • Chakrabarti S.
      • Tella S.H.
      • Kommalapati A.
      • Huffman B.M.
      • Yadav S.
      • Riaz I.B.
      • et al.
      Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
      Case-reports on the use of ICIs are limited and response varies from progression to CR.
      • Bauer U.
      • Mogler C.
      • Braren R.F.
      • Algul H.
      • Schmid R.M.
      • Ehmer U.
      Progression after immunotherapy for fibrolamellar carcinoma.
      Notably CR was achieved in a patient with PD-L1 expression of 10%.
      • Chakrabarti S.
      • Tella S.H.
      • Kommalapati A.
      • Huffman B.M.
      • Yadav S.
      • Riaz I.B.
      • et al.
      Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma.
      Therefore, further research is required to define the role of ICIs in the treatment of FLHCC (Table 2).
      HCC/CCC is another rare subtype of primary liver tumour characterised by the presence of both hepatocellular and cholangiocellular components in biopsies or surgical specimens.
      • Nagtegaal I.D.
      • Odze R.D.
      • Klimstra D.
      • Paradis V.
      • Rugge M.
      • Schirmacher P.
      • et al.
      The 2019 WHO classification of tumours of the digestive system.
      Aetiologically, HCC/CCC share common risk factors with conventional HCC and are mainly based on chronic inflammatory liver diseases. Currently, treatment allocations are based on tumour stage, liver function and the patient's performance status. Patients are mainly treated according to guidelines of either HCC or CCC depending on the dominant type in diagnosed tumour and/or metastases. While integrative approaches and characterisation of genetic alterations identified druggable targets such as fibroblast growth factor receptor 2 (FGFR2) gene fusions and isocitrate dehydrogenase (IDH) mutations in intrahepatic CCC, molecular alterations of HCC/CCC remain poorly characterised.
      • Chakrabarti S.
      • Kamgar M.
      • Mahipal A.
      Targeted therapies in advanced biliary tract cancer: an evolving paradigm.
      One of the largest molecular characterisation studies to date included 133 Asian HCC/CCC cases and revealed distinct subtypes with different clinical and molecular features.
      • Xue R.
      • Chen L.
      • Zhang C.
      • Fujita M.
      • Li R.
      • Yan S.M.
      • et al.
      Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes.
      However, further comprehensive molecular analyses are necessary to better understand the complexity of distinct subgroups and to pave the way for new and effective targeted treatment approaches (Table 2).

      Patients with decompensated cirrhosis (Child-Pugh B and C)

      HCC typically occurs on the background of cirrhosis, whose natural course leads to hepatic decompensation and organ failure. Being a strong confounder, patients with impaired liver function are usually excluded from clinical trials (see Table 1). In fact, the only successful registrational phase III trial which was not limited to Child-Pugh class A was the SHARP trial which tested sorafenib (Table 1). In addition, hepatotoxicity is a risk with currently approved systemic treatments, particularly MKIs, which should therefore be used with caution in clinical practice (Table 2). Data on their safety and efficacy are limited in patients with Child-Pugh B and even more so in those with Child-Pugh C.
      A meta-analysis of 30 studies evaluating sorafenib as first-line treatment in a total of 8,678 patients with advanced HCC revealed that Child-Pugh B liver function is associated with worse OS (p = 0.001).
      • McNamara M.G.
      • Slagter A.E.
      • Nuttall C.
      • Frizziero M.
      • Pihlak R.
      • Lamarca A.
      • et al.
      Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis.
      The GIDEON study, which was included in the aforementioned meta-analysis, quantified median OS in the intention-to-treat population (n = 3,213) as 13.6 vs. 5.2 vs. 2.6 months in Child-Pugh A, B and C patients, respectively.
      • Marrero J.A.
      • Kudo M.
      • Venook A.P.
      • Ye S.L.
      • Bronowicki J.P.
      • Chen X.P.
      • et al.
      Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.
      With regard to lenvatinib, a retrospective single-centre study including Child-Pugh A, B and C patients reported a median OS of 8.5 months, with Child-Pugh B and C being associated with poor survival.
      • San-Chi C.
      • Chao Y.
      • Chen M.H.
      Lenvatinib for the treatment of HCC: a single institute experience.
      In the second-line setting, ramucirumab showed no trend towards a response in Child-Pugh B patients in the initial, negative REACH trial,
      • Zhu A.X.
      • Park J.O.
      • Ryoo B.Y.
      • Yen C.J.
      • Poon R.
      • Pastorelli D.
      • et al.
      Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.
      while being associated with a higher rate of grade ≥3 AEs.
      • Zhu A.X.
      • Baron A.D.
      • Malfertheiner P.
      • Kudo M.
      • Kawazoe S.
      • Pezet D.
      • et al.
      Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by Child-Pugh score.
      As a consequence, the following REACH-2 trial, which tested ramucirumab in patients with baseline alpha-fetoprotein levels of ≥400 ng/ml, excluded patients with a Child-Pugh score >6.(5) While only patients with Child-Pugh A liver function were included in the CELESTIAL trial, a retrospective analysis of patients whose liver function deteriorated to Child-Pugh B by week 8 demonstrated the manageable safety profile and efficacy of cabozantinib in this subgroup.

      El-Khoueiry A, Meyer T, Cheng A, Rimassa L, Sen S, Milwee S, et al. Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib vs. placebo. abstract ESMO 2020;SO-9.

      The first ICI to be tested in Child-Pugh B patients was nivolumab as part of the CheckMate 040-trial (cohort 5). The disease control rate was 55.1% and the median OS 7.6 months.
      • Kudo M.
      • Matilla A.
      • Santoro A.
      • Melero I.
      • Gracian A.C.
      • Acosta-Rivera M.
      • et al.
      Checkmate-040: nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status.
      Clinical trials including patients with comorbidities are needed to provide robust evidence for their systemic treatment.
      In conclusion, MKIs and ICIs can be used with a reasonable degree of caution in patients with Child-Pugh B liver function. However, local availability and labelling issues may restrict the discussed treatment options. Due to the lack of a demonstrated therapeutic benefit, patients with Child-Pugh C cirrhosis should not receive targeted therapy but best supportive care.

      Elderly patients

      The incidence of HCC is age dependent, although age at diagnosis varies according to the aetiology of the underlying liver disease. Most diagnoses of HCC occur in patients ≥60 years in Japan, North America and European countries while in Asia (excluding Japan), and in most African countries, where chronic HBV infection is prevalent, HCC is diagnosed at ages ranging between 30 and 60 years.
      • Yang J.D.
      • Hainaut P.
      • Gores G.J.
      • Amadou A.
      • Plymoth A.
      • Roberts L.R.
      A global view of hepatocellular carcinoma: trends, risk, prevention and management.
      While there is no agreement on the age cut-off that defines an elderly population, the median age of patients enrolled in most trials testing systemic agents for HCC is roughly 65 years.
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      • 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.
      • 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.
      • 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.
      • 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 alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • Kudo M.
      • Hsu C.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      • Zhu A.X.
      • Finn R.S.
      • Edeline J.
      • Cattan S.
      • Ogasawara S.
      • Palmer D.
      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Considering age as a prognostic factor, current evidence does not suggest significant differences in OS, as long as 65 years is the selected cut-off (Table 3).
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      • 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.
      • 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.
      • 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.
      • 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 alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • Kudo M.
      • Hsu C.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      • Zhu A.X.
      • Finn R.S.
      • Edeline J.
      • Cattan S.
      • Ogasawara S.
      • Palmer D.
      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      • 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.
      • Yau T.P.J.
      • Finn R.S.
      • Cheng A.
      • Mathurin P.
      • Edeline J.
      • Kudo M.
      • et al.
      LBA38_PR: CheckMate 459: a randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC).
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      While the SHARP trial did not report subgroup analyses by age,
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      the subsequent Asia-Pacific trial did not establish a survival benefit from sorafenib over placebo in older patients
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      although only 32 patients were in fact aged >65 years. Nonetheless, a pooled analysis that involved both trials did not detect prognostic differences between patients aged <75 years and those aged ≥75 years, confirming the benefit of sorafenib regardless of age.
      • Bruix J.
      • Cheng A.L.
      • Meinhardt G.
      • Nakajima K.
      • De Sanctis Y.
      • Llovet J.
      Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies.
      Other studies demonstrated that age was not prognostic but was independently related to treatment discontinuation due to intolerance.
      • Iavarone M.
      • Cabibbo G.
      • Piscaglia F.
      • Zavaglia C.
      • Grieco A.
      • Villa E.
      • et al.
      Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
      A global trend towards earlier discontinuations emerges in elderly patients,
      • Morimoto M.
      • Numata K.
      • Kondo M.
      • Hidaka H.
      • Takada J.
      • Shibuya A.
      • et al.
      Higher discontinuation and lower survival rates are likely in elderly Japanese patients with advanced hepatocellular carcinoma receiving sorafenib.
      ,
      • Edeline J.
      • Crouzet L.
      • Le Sourd S.
      • Larible C.
      • Brunot A.
      • Le Roy F.
      • et al.
      Sorafenib use in elderly patients with hepatocellular carcinoma: caution about use of platelet aggregation inhibitors.
      even though more tailored approaches with closer follow-up consultations are felt to improve long-term compliance.
      • Tada T.
      • Kumada T.
      • Hiraoka A.
      • Michitaka K.
      • Atsukawa M.
      • Hirooka M.
      • et al.
      Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: a multicenter analysis with propensity score matching.
      ,

      Li D, Toh H, Merle P, Tsuchiya K, Hernandez S, Shao H, et al. Atezolizumab + bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma (HCC): results from older adults enrolled in IMbrave150. ESMO World Congress on Gastrointestinal Cancer 2020;Virtual. Abstract 0-8.

      In contrast, no significant differences were reported in terms of AEs in patients treated with lenvatinib who were analysed according to a cut-off age of 75 years.
      • Tada T.
      • Kumada T.
      • Hiraoka A.
      • Michitaka K.
      • Atsukawa M.
      • Hirooka M.
      • et al.
      Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: a multicenter analysis with propensity score matching.
      Also, in the IMbrave150 trial, similar safety profiles and patient-reported outcomes (PROs) were observed in patients aged <65 year and ≥65 years, who received the atezolizumab-bevacizumab combination.

      Li D, Toh H, Merle P, Tsuchiya K, Hernandez S, Shao H, et al. Atezolizumab + bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma (HCC): results from older adults enrolled in IMbrave150. ESMO World Congress on Gastrointestinal Cancer 2020;Virtual. Abstract 0-8.

      Table 3Survival outcomes in phase III pivotal trials in patients <65 years and patients ≥65 years.
      TrialTreatment arms

      Number of patients (N)
      Median age, years (range)Patients ≥65 yearsHR OS (<65 years)HR OS (≥65 years)
      SHARP
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      Sorafenib (299)

      Placebo (303)
      65 (53–76)

      66 (56–76)
      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.
      Lenvatinib (478)

      Sorafenib (476)
      63 (20–88)

      62 (22–88)
      44%

      41%
      0.94 (95% CI 0.77–1.15)0.84 (95% CI 0.66–1.07)
      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.
      Regorafenib (379)

      Placebo (194)
      64 (54–71)

      62 (55–68)
      45%
      Refers to the overall cohort.
      0.65 (95% CI 0.49–0.87)0.74 (95% CI 0.54–1.02)
      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.
      Cabozantinib (470)

      Placebo (237)
      64 (22–86)

      64 (24–86)
      49%

      48%
      0.81 (95% CI 0.62–1.05)0.74 (95% CI 0.56–0.97)
      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 alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Ramucirumab (197)

      Placebo (95)
      64 (58–73)

      64 (56–71)
      48%

      48%
      0.64 (95% CI 0.42–0.95)0.84 (95% CI 0.42–0.95)
      CheckMate 459
      • Yau T.P.J.
      • Finn R.S.
      • Cheng A.
      • Mathurin P.
      • Edeline J.
      • Kudo M.
      • et al.
      LBA38_PR: CheckMate 459: a randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC).
      Nivolumab (371)

      Sorafenib (372)
      65 (19–89)

      65 (20–87)
      50%

      53%
      0.80 (95% CI 0.63–1.02)0.88 (95% CI 0.68–1.12)
      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.
      Pembrolizumab (278)

      Placebo (135)
      67 (18–91)

      65 (23–89)
      58%
      Refers to the overall cohort.
      0.75 (95% CI 0.52–1.09)0.92 (95% CI 0.65–1.30)
      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.
      Atezolizumab + bevacizumab (336)

      Sorafenib (165)
      64 (26–88)

      66 (33–87)
      47%

      55%
      0.59 (95% CI 0.38–0.91)0.58 (95% CI 0.36–0.92)
      HR, hazard ratio; n.a., not available; OS, overall survival.
      Refers to the overall cohort.
      For second-line treatments, subgroup analyses by age indicate slight differences in hazard ratio that were consistent with the OS benefit provided by the investigational agent. In the CELESTIAL study, the proportions of patients aged <65 year and older who received anticancer therapy after cabozantinib were comparable, suggesting that access to additional treatments is independent of age.
      • Rimassa L.
      • Cicin I.
      • Blanc J.-F.
      • Klümpen H.J.
      • Zagonel V.
      • Tran A.
      • et al.
      Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC).
      In patients with alpha-fetoprotein levels ≥400 ng/ml, no differences were observed in terms of efficacy, safety and PROs for ramucirumab, according to 3 different age ranges: <65 years, ≥65 to <75, ≥75.
      • Kudo M.
      • Galle P.R.
      • Llovet J.M.
      • Finn R.S.
      • Vogel A.
      • Motomura K.
      • et al.
      Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.
      Whilst progressive shifts in recruitment age
      • 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.
      ,
      • 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.
      ,
      • Yau T.P.J.
      • Finn R.S.
      • Cheng A.
      • Mathurin P.
      • Edeline J.
      • Kudo M.
      • et al.
      LBA38_PR: CheckMate 459: a randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (AHCC).
      indicate easier handling of targeted and immuno-oncology therapies, the inter-quartile ranges of baseline ages reported in major trials suggest that patients aged >70 years are underrepresented.
      • 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.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Given the growing need to appraise patients' functioning besides routine performance measures, frailty may provide more accurate metrics.
      • Mohile S.G.
      • Dale W.
      • Somerfield M.R.
      • Schonberg M.A.
      • Boyd C.M.
      • Burhenn P.S.
      • et al.
      Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology.
      The use of frailty metrics to guide treatment modifications is gaining tremendous interest in elderly cancer patients.
      • Jain R.K.
      • Lee J.J.
      • Hong D.
      • Markman M.
      • Gong J.
      • Naing A.
      • et al.
      Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse.
      ,
      • Miyamoto S.
      • Azuma K.
      • Ishii H.
      • Bessho A.
      • Hosokawa S.
      • Fukamatsu N.
      • et al.
      Low-dose erlotinib treatment in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer: a multicenter phase 2 trial.
      With respect to sorafenib, reduced doses were indeed shown to increase survival,
      • Iavarone M.
      • Cabibbo G.
      • Piscaglia F.
      • Zavaglia C.
      • Grieco A.
      • Villa E.
      • et al.
      Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.
      lower the incidence of severe AEs,
      • Morimoto M.
      • Numata K.
      • Kondo M.
      • Kobayashi S.
      • Ohkawa S.
      • Hidaka H.
      • et al.
      Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: a propensity score analysis.
      and reduce treatment discontinuation.
      • Reiss K.A.
      • Yu S.
      • Mamtani R.
      • Mehta R.
      • D'Addeo K.
      • Wileyto E.P.
      • et al.
      Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multi-institutional study.
      In conclusion, current evidence supports reduced starting doses of sorafenib and timely clinical follow-up for the early management of AEs, particularly in patients aged >75 years (Table 2). That said, most available information in elderly patients comes from studies exploring sorafenib, while less is known regarding other agents.

      Patients with a significant bleeding history

      In patients with cirrhosis, the actuarial risk of variceal bleeding is up to 15% after variceal ligation
      • Sarin S.K.
      • Lamba G.S.
      • Kumar M.
      • Misra A.
      • Murthy N.S.
      Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding.
      and is largely dependent on clinical parameters pertaining to liver function, but not coagulation disorders.
      • Northup P.G.
      • Caldwell S.H.
      Coagulation in liver disease: a guide for the clinician.
      In this context, antiangiogenic agents may confer an increased risk, which has long been acknowledged,
      • Hershman D.L.
      • Wright J.D.
      • Lim E.
      • Buono D.L.
      • Tsai W.Y.
      • Neugut A.I.
      Contraindicated use of bevacizumab and toxicity in elderly patients with cancer.
      given the interplay with concomitant cirrhosis (Table 1).
      Besides variceal bleeding, bleeding events that occur relatively frequently with antiangiogenics include epistaxis and gingival bleeding, which have been reported in patients with HCC
      • Pomej K.
      • Scheiner B.
      • Park D.
      • Bauer D.
      • Balcar L.
      • Meischl T.
      • et al.
      Vascular complications in patients with hepatocellular carcinoma treated with sorafenib.
      as well as in non-HCC contexts.
      • Goyal L.
      • Zheng H.
      • Yurgelun M.B.
      • Abrams T.A.
      • Allen J.N.
      • Cleary J.M.
      • et al.
      A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma.
      ,
      • Casak S.J.
      • Fashoyin-Aje I.
      • Lemery S.J.
      • Zhang L.
      • Jin R.
      • Li H.
      • et al.
      FDA approval summary: ramucirumab for gastric cancer.
      Such minor bleeding events do not require medical attention and their impact can be minimised with adequate patient education.
      A pooled analysis including randomised trials of sorafenib in HCC confirmed that a significant risk of any-grade bleeding events exists, but did not substantially differ from renal cancer trials: 6.65% with sorafenib vs. 3.37% in control arms (p = 0.04).
      • Duffy A.
      • Wilkerson J.
      • Greten T.F.
      Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies.
      The rate of bleeding events (grade 3–5) related to ramucirumab was similar (1%) in the experimental and placebo arms of the REACH-2 trial,
      • 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 alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      whereas the KEYNOTE-240 trial reported 3 such grade 5 events (1%) with pembrolizumab and none with placebo.
      • 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.
      Following 3 episodes of gastrointestinal haemorrhage (including a fatal one), 2 earlier trials testing bevacizumab were amended to provide an upper endoscopy in patients with oesophageal varices during screening procedures.
      • Siegel A.B.
      • Cohen E.I.
      • Ocean A.
      • Lehrer D.
      • Goldenberg A.
      • Knox J.J.
      • et al.
      Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma.
      ,
      • Thomas M.B.
      • Morris J.S.
      • Chadha R.
      • Iwasaki M.
      • Kaur H.
      • Lin E.
      • et al.
      Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma.
      Despite the enrolment of patients with Child-Pugh B liver function, no further gastrointestinal haemorrhages were reported once screening measures were implemented.
      • Thomas M.B.
      • Morris J.S.
      • Chadha R.
      • Iwasaki M.
      • Kaur H.
      • Lin E.
      • et al.
      Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma.
      Policies mandating the exclusion of patients at risk of variceal bleeding might explain, at least in part, the absence of any high-grade bleeding events in further trials of MKI.
      • 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.
      ,
      • 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.
      ,
      • Duffy A.G.
      • Ma C.
      • Ulahannan S.V.
      • Rahma O.E.
      • Makarova-Rusher O.
      • Cao L.
      • et al.
      Phase I and preliminary phase II study of TRC105 in combination with sorafenib in hepatocellular carcinoma.
      More recently, in the IMbrave150 trial, bleeding events (any grade) were experienced by 25.2% of patients in the atezolizumab plus bevacizumab arm, and 17.3% of patients in the sorafenib arm. Grade 3–4 bleeding was reported in 6.4% of the patients under bevacizumab plus atezolizumab, but did not differ from the sorafenib arm (5.8%).
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Although upper endoscopy and primary prophylaxis were requested within 6 months prior to treatment start, fatal bleeding events or perforated ulcers occurred in 6 patients (1.8%) assigned to combination, and in 1 patient (<1%) assigned to sorafenib. Since patients with deteriorating liver function are more likely to have portal hypertension and higher risks of bleeding, data from the IMbrave150 trial cannot be extrapolated to these patients (Table 2). Despite a rate of severe bleeding events similar to that reported in prior studies investigating bevacizumab, real-world studies of atezolizumab plus bevacizumab are necessary to better assess the generalisability of the IMbrave150 trial.
      Clinicians must pay extra attention to these special populations and apply currently approved treatments with caution.
      Most importantly, screening for varices has led to a significant decline in variceal bleeding and related mortality over the last decades.
      • Carbonell N.
      • Pauwels A.
      • Serfaty L.
      • Fourdan O.
      • Levy V.G.
      • Poupon R.
      Improved survival after variceal bleeding in patients with cirrhosis over the past two decades.
      In patients newly diagnosed with cirrhosis, the benefit of such screening measures is currently endorsed by several consensus guidelines.
      • Garcia-Tsao G.
      • Abraldes J.G.
      • Berzigotti A.
      • Bosch J.
      Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
      ,
      European Association for Study of Liver
      EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis.

      Patients undergoing haemodialysis

      The overall incidence of HCC among patients with chronic kidney disease (CKD) was estimated to be approximately 2.03 per 1,000 person years.
      • Hwang J.C.
      • Weng S.F.
      • Weng R.H.
      High incidence of hepatocellular carcinoma in ESRD patients: caused by high hepatitis rate or ‘uremia’? a population-based study.
      Patients undergoing haemodialysis are often diagnosed with more advanced HCC compared to non-dialysis patients, resulting in a worse prognosis. In fact, patients on haemodialysis are frequently not screened for HCC, even if a considerable percentage of them, especially those who are HCV positive, are at risk of HCC.
      • Toyoda H.
      • Hiraoka A.
      • Tada T.
      • Michitaka K.
      • Takaguchi K.
      • Tsuji K.
      • et al.
      Characteristics and prognosis of hepatocellular carcinoma in Japanese patients undergoing dialysis.
      Therefore, a collaborative effort among HCC and CKD specialists is crucial to improve patient outcomes (Table 2).
      Owing to their exclusion from clinical trials, there is very limited data available on patients with HCC and CKD under haemodialysis (Table 1). A phase I and pharmacokinetic study evaluated sorafenib in patients with hepatic or renal dysfunction.
      • Miller A.A.
      • Murry D.J.
      • Owzar K.
      • Hollis D.R.
      • Kennedy E.B.
      • Abou-Alfa G.
      • et al.
      Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.
      This study consisted of multiple cohorts including 17 patients with HCC and 17 patients on haemodialysis. However, no details regarding the cancer type and liver function status of patients on haemodialysis were provided. Therefore, no specific conclusions can be drawn for patients with HCC undergoing haemodialysis. However, for patients under haemodialysis, a starting dose of sorafenib of 200 mg daily was suggested, considering dose escalation if the drug was well tolerated.
      • Miller A.A.
      • Murry D.J.
      • Owzar K.
      • Hollis D.R.
      • Kennedy E.B.
      • Abou-Alfa G.
      • et al.
      Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.
      A large European and Latin American retrospective multicentre real-world study reported data on 6,156 patients with HCC treated with sorafenib, of whom 22 (0.36%) had CKD and required haemodialysis.
      • Diaz-Gonzalez A.
      • Sanduzzi-Zamparelli M.
      • da Fonseca L.G.
      • Di Costanzo G.G.
      • Alves R.
      • Iavarone M.
      • et al.
      International and multicenter real-world study of sorafenib-treated patients with hepatocellular carcinoma under dialysis.
      Seventeen patients (77.3%) required at least 1 dose reduction, mostly due to clinical deterioration or diarrhoea. Further AEs included HFSR and liver decompensation. Treatment was discontinued in 18 (77.8%) patients because of disease progression and in 22.2% of patients because of AEs, half of them deemed sorafenib-related (1 diarrhoea and 1 arterial thrombosis). Seven patients (31.8%) had a grade ≥3 serious AE. Although none of the patients received second-line treatment, median OS was 17.5 months (95% CI 7.2–24.5).
      • Diaz-Gonzalez A.
      • Sanduzzi-Zamparelli M.
      • da Fonseca L.G.
      • Di Costanzo G.G.
      • Alves R.
      • Iavarone M.
      • et al.
      International and multicenter real-world study of sorafenib-treated patients with hepatocellular carcinoma under dialysis.
      Based on these results sorafenib use seems feasible in patients under haemodialysis, with outcomes similar to those in patients without haemodialysis. However, the lack of randomised clinical trial data urges caution and an overall clinical evaluation is warranted before administering sorafenib to these patients (Table 2). Furthermore, these results cannot be extrapolated to other systemic treatments such as other MKIs, antiangiogenics, and ICIs. However, a recently published review on targeted and immune therapies for patients with metastatic renal carcinoma undergoing haemodialysis, including 55 patients treated with sorafenib, 18 patients treated with nivolumab, and 6 patients treated with bevacizumab, concluded that haemodialysis did not seem to modify the expected efficacy and safety of these drugs.
      • Klajer E.
      • Garnier L.
      • Goujon M.
      • Schlurmann-Constans F.
      • Mery B.
      • Nguyen Tan Hon T.
      • et al.
      Targeted and immune therapies among patients with metastatic renal carcinoma undergoing hemodialysis: a systemic review.
      Therefore, it seems that these agents can be safely used in patients undergoing haemodialysis, although careful monitoring is recommended in this special population because of frailty and comorbidities associated with CKD.

      Patients with vascular invasion or portal vein thrombosis

      It is well known that patients with HCC are at a high risk of pathological thrombosis. PVT is the most common thrombotic complication in patients with HCC and cirrhosis.
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      Compared to cirrhotic patients without malignancy, the incidence of PVT in patients with HCC has been reported to be more than doubled (24.4% vs. 11.4%; p = 0.05).
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      Non-malignant thromboses have to be distinguished from malignant thromboses, since macrovascular tumour invasion (MVI) has important therapeutic consequences. MVI, being most commonly a portal vein tumour thrombosis (PVTT), is an exclusion criterion for curative therapies such as OLT (Table 1).
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      New evidence and perspectives on the management of hepatocellular carcinoma with portal vein tumor thrombus.
      Interestingly, the presence of either MVI/PVTT or PVT is associated with poor survival in patients with HCC.
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      Studies have shown that for patients with PVTT, prognosis depends on grade, with median survivals of just 2–5 months reported in patients with PVTT of the main trunk.
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      Patients with HCC and diagnosed PVTT have advanced disease (BCLC stage C). Several guidelines recommend systemic therapies for patients with HCC and PVTT.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
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      Most data are based on sorafenib treatment. Median survival time was slightly longer in the sorafenib group (8.1 months) than in the placebo group (4.9 months) in a subgroup analysis of the phase III SHARP trial of patients with HCC and PVTT.
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      Recent randomised studies stratified or excluded patients with pronounced PVTT. Lenvatinib has shown to be non-inferior to sorafenib in the first-line setting, but patients with main portal trunk invasion were excluded from the phase III study (Table 1).
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      A recent retrospective analysis observed favourable outcomes for patients with advanced HCC and pronounced PVTT (grade 3/4) treated with lenvatinib in comparison to sorafenib.
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      Thus, current data suggest that lenvatinib is a viable option in this setting as well.
      Especially in Eastern countries, different treatment approaches including liver resection (144), transarterial chemoembolisation,
      • Kokudo T.
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      radiotherapy,
      • Silva J.P.
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      • Clarke C.N.
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      • et al.
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      radioembolisation with yttrium-90,
      • Chow P.K.H.
      • Gandhi M.
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      • Ong J.
      • et al.
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      hepatic arterial infusion chemotherapy as well as combination therapies with sorafenib for patients with HCC and PVTT have been investigated and have provided promising results for specific conditions.
      • Choi J.H.
      • Chung W.J.
      • Bae S.H.
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      • Song M.J.
      • Kim Y.S.
      • et al.
      Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis.
      However, comparing the efficacy of different treatment modalities in these studies is difficult due to patient heterogeneity. Thus, the treatment of patients with HCC and PVTT remains challenging. Future recommendations need to be based on clear evidence from prospective randomised trials in larger patient cohorts (Table 2).

      Conclusion

      As outlined, there are various groups of patients with HCC and specific comorbidities or disease features who require extra clinical attention. These groups reflect the heterogeneity of patients encountered in real-world practice who are not adequately represented in clinical trials, because they do not meet the criteria of the “standard” patient with HCC. The main reason for excluding patients with certain comorbidities, such as vascular invasion or decompensated cirrhosis, is the well-known negative impact of these comorbidities on prognosis, which potentially confounds trial data. This practice has resulted in a general lack of data on treatment safety and efficacy in the described patient groups, which poses a significant and unmet medical need. The challenge of treating HCC in these special populations should be an incentive to design management algorithms tailored to patients' needs and to conduct clinical trials that address open questions (Fig. 1), which could help to define best practice and identify novel treatments. Both the heterogeneity of HCC and the heterogeneity of affected patients make research and clinical management challenging. Yet it is essential that future research and clinical management reflect this heterogeneity.
      Figure thumbnail gr1
      Fig. 1Considerations to optimise treatment, care, and outcomes in special HCC populations.
      HCC, hepatocellular carcinoma.

      Abbreviations

      AE, adverse events; AIH, autoimmune hepatitis; cART, combined antiretroviral therapy; CKD, chronic kidney disease; CR, complete response; CVD, cardiovascular disease; FLHCC, fibrolamellar HCC; HCC, hepatocellular carcinoma; HCC/CCC, mixed hepatocellular/cholangiocellular carcinoma; HFSR, hand-foot skin reaction; ICI, immune checkpoint inhibitor; irAE, immune-related AE; mTOR, mammalian target of rapamycin; MVI, macrovascular tumour invasion; NAFLD, non-alcoholic fatty liver disease; OLT, orthotopic liver transplantation; OS, overall survival; PBC, primary biliary cholangitis; PD-1, programmed cell death 1; PLWH, people living with HIV; PROs, patient-reported outcomes; PVT, portal vein thrombosis; PVTT, portal vein tumour thrombosis.

      Financial support

      The authors received no financial support to produce this manuscript.

      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

      LR reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. NP reports receiving consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly; travel fees from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. CC reports receiving consulting fees from MSD and lectures fees from EISAI. FF reports receiving consulting fees from Roche; lectures fees from Lilly and Pfizer. 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

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