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The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma

  • Delia D’Avola
    Affiliations
    Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain

    Centro de Investigación Bio Medica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
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  • Alessandro Granito
    Affiliations
    Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

    Department of Medical and Surgical Sciences, University of Bologna, Italy
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  • Manuel de la Torre-Aláez
    Affiliations
    Liver Unit, Internal Medicine Department, Clinica Universidad de Navarra, Pamplona and Madrid, Spain
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  • Fabio Piscaglia
    Correspondence
    Corresponding author. Address: Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138, Bologna, Italy; Tel.: +39 051 214 2568, fax +39 051 214 2725.
    Affiliations
    Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

    Department of Medical and Surgical Sciences, University of Bologna, Italy
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Published:November 15, 2021DOI:https://doi.org/10.1016/j.jhep.2021.11.013

      Summary

      The aim of any oncological treatment is not just to eliminate the tumour, but to maximise patient survival and quality of life. Since the liver has a vital function, any radical treatment that severely compromises liver function will result in a shortening of life expectancy, rather than a prolongation. Furthermore, even non-severe liver damage may prevent the delivery of further effective therapies. This is particularly important in the case of hepatocellular carcinoma (HCC), as it is associated with underlying cirrhosis in most patients – cirrhosis itself is not only a potentially lethal disease and independent prognostic factor in HCC, but it also makes liver function fragile. Accordingly, some information about liver dysfunction is included in most staging systems for HCC and can be used to guide the selection of treatments that the functional liver reserve can tolerate. Unfortunately, the prediction of functional damage to the liver in the case of antitumor treatments is very challenging and still suboptimal in any given patient. Moreover, while the assessment of functional reserve can now be used to avoid postoperative liver failure in the surgical setting, its use has been less well clarified for non-surgical therapies, which is of particular relevance today, as several lines of effective non-surgical treatments, including systemic therapies, have become available. The present article will a) critically review the implications of the assessment of liver functional reserve in patients with HCC, b) illustrate the available tools to assess liver functional reserve and c) discuss the role of functional assessment for each type of non-surgical therapy for HCC.

      Keywords

      Introduction

      The occurrence of hepatocellular carcinoma (HCC) is favoured by pre-existing chronic liver disease
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      and indeed the vast majority of patients with HCC have advanced liver fibrosis or cirrhosis. Cirrhosis is itself a potentially lethal disease, following decompensation and terminal liver failure, and patients with cirrhosis are often in a fragile balance between general and liver-specific health conditions. Therefore, patients with HCC and cirrhosis may die exclusively of tumour progression (with no liver failure), of terminal cirrhotic liver failure (with only a limited tumour burden), or from the combination of both.
      Therefore, the degree of liver dysfunction is an independent prognostic factor in patients with HCC and different measures of liver dysfunction can stratify patients with HCC into separate prognostic categories regardless of tumour burden.
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      Validation of modified ALBI grade for more detailed assessment of hepatic function in hepatocellular carcinoma patients: a multicenter analysis.
      This is why the assessment of liver function was included in most staging systems for HCC, which are termed “integrated staging systems”. The most evolved staging systems for HCC provide not only prognostic information, but also information about the recommended treatment choices for each stage.
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      ,
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      The concept of liver functional reserve was first introduced in the setting of oncological liver surgery and refers to the ability of the remnant liver to adequately maintain hepatic function in the postoperative period. The same concept may be applied to non-surgical therapies, since these may also be associated with a potential risk of functional damage to the liver. To this end, it is important to remember that the aim of any oncological treatment must be to maximise patient survival and quality of life, and not just to eliminate the tumour.
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      Design and endpoints of clinical trials in hepatocellular carcinoma.
      Since the liver has a vital function, any radical treatment of liver tumours that severely compromises liver function will result in a shortening rather than a lengthening of life expectancy, despite being a radical tumour therapy.
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      Design and endpoints of clinical trials in hepatocellular carcinoma.
      However, even a non-severe, subclinical, worsening of liver function may have a deleterious impact, not in terms of directly causing patient death, but because it could impede the delivery of subsequent effective therapies. The goal of predicting a sufficient liver reserve for any given HCC treatment has in fact become even more pertinent in recent times due to the rapidly expanding potential of single and combined systemic therapies.
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      Surgery and portal hypertension.
      Unfortunately, we still lack predictors of individual response to pharmacological therapies, but there is a potential for good response in any line of systemic treatment, provided liver function is preserved. This is particularly relevant when choosing locoregional therapies. Our ability to predict the impact of such therapies on liver function in any given patient is far from optimal. In fact, even within any tumour stage, the expected deterioration in liver function induced by any locoregional treatment heavily depends on the tumour location, tumour burden and on the expertise of local operators, which is difficult to include in any widely applicable score.
      The present article will illustrate the different tools available to assess the liver functional reserve and will discuss the role of functional assessment in the setting of each type of non-surgical therapy for HCC. Such information is expected to be relevant for clinicians at every stage in the management of HCC (Fig. 1).
      The concept of liver functional reserve was first introduced in the setting of oncological liver surgery and refers to the ability of the remnant liver to adequately maintain hepatic function in the postoperative period. However, considering the degree of liver functional reserve in non-surgical HCC therapies is also important, since these may also be associated with a potential risk of functional liver damage.
      Figure thumbnail gr1
      Fig. 1Stepwise process of treatment general planning in patients with HCC.

      Tools for the estimation of liver functional reserve

      Blood tests such as bilirubin, prothrombin time and albumin may provide a rough estimation of liver functional reserve, but the performance of these parameters individually is poor. The Child-Pugh score has been the most used method for estimating liver function since the second half of the past century.
      • Child C.G.
      • Turcotte G.
      Surgery and portal hypertension.
      The main limitations of the Child-Pugh score are that it was designed to assess the presence of clinical decompensation and accordingly relies on the clinical and relatively subjective assessment of ascites and hepatic encephalopathy, which may impair interobserver reproducibility, and that it cannot be accurately calculated retrospectively for research purposes. Moreover, in keeping with its initial goal it does not perform well in discriminating among different grades of compensated patients.
      The model for end-stage liver disease (MELD) score is a newer system based solely on biochemical variables (creatinine, international normalised ratio [INR] and bilirubin in the first version, with the addition of sodium in the last version) that was initially proposed for the prediction of survival in patients undergoing transjugular intrahepatic portosystemic shunt.
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      • Rank J.
      • Ter Borg P.C.J.
      A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.
      MELD provides a more granular distinction of the degree of dysfunction in more severely ill patients than the Child-Pugh score, since it is continuous, with no thresholds for producing the score points. It has since become one of the most widely used systems, replacing the Child-Pugh score for liver transplant prioritisation, given its higher accuracy to predict survival in the sickest patients.
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      A MELD-based model to determine risk of mortality among patients with acute variceal bleeding.
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      Longitudinal assessment of prognostic factors for patients with hepatorenal syndrome in a tertiary center.
      • Bernardi M.
      • Gitto S.
      • Biselli M.
      The MELD score in patients awaiting liver transplant: strengths and weaknesses.
      However, in terms of evaluation of liver functional reserve, the MELD score is no more accurate than other systems, at least in a surgical setting.
      • Wang Y.Y.
      • Zhao X.H.
      • Ma L.
      • Ye J.Z.
      • Wu F.X.
      • Tang J.
      • et al.
      Comparison of the ability of Child-Pugh score, MELD score, and ICG-R15 to assess preoperative hepatic functional reserve in patients with hepatocellular carcinoma.
      More recently, the ALBI grade, based only on albumin and bilirubin (as continuous variables), has been introduced to predict prognosis in patients with HCC.
      • Johnson P.J.
      • Berhane S.
      • Kagebayashi C.
      • Satomura S.
      • Teng M.
      • Reeves H.L.
      • et al.
      A nssessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach - the albi grade.
      It can be easily calculated retrospectively, as the included variables are available in almost all patients. Moreover, it enables patients to be stratified into 3 groups with statistical differences in survival (ALBI grades 1, 2 and 3 represent best to worst survival, respectively).
      Even within the Child-Pugh class A, the ALBI score may identify different survival probabilities after surgical and non-surgical therapies,
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      • Su Z.Y.
      • Huang J.F.
      • Lu S.D.
      • Xiang B.D.
      • et al.
      Albumin-bilirubin versus Child-Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma.
      ,
      • Gui B.
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      • Lu S.-E.
      • Foltz G.M.
      • Hasan O.
      • et al.
      Assessment of the albumin-bilirubin (ALBI) grade as a prognostic indicator for hepatocellular carcinoma patients treated with radioembolization.
      confirming its ability to provide a more granular assessment of liver functional reserve compared to the Child-Pugh score, including in compensated liver disease and after a variety of treatments, regardless of tumour stage.
      • Pinato D.J.
      • Sharma R.
      • Allara E.
      • Yen C.
      • Arizumi T.
      • Kubota K.
      • et al.
      The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma.
      ,
      • Hickey R.
      • Mouli S.
      • Kulik L.
      • Desai K.
      • Thornburg B.
      • Ganger D.
      • et al.
      Independent analysis of albumin-bilirubin grade in a 765-patient cohort treated with transarterial locoregional therapy for hepatocellular carcinoma.
      Beside biochemical tests, other methods for estimating the liver functional reserve have been utilised in clinical practice, but their use in non-surgical settings is still very limited and poorly validated. Most of the tests, reported in detail in Table 1 and Table S1, have been utilised to predict the capacity of the liver to adequately tolerate surgical resection.
      Table 1Methods for the estimation of liver functional reserve and main applications.
      MethodVariablesAssessmentsMain applications
      Child-Pugh scoreBilirubin, albumin, prothrombin time, ascites, encephalopathyEstimation of global liver function and portal hypertension (indirect)Surgery: prediction of liver failure and survival

      Liver transplantation: prediction of survival on waiting list

      TACE: prediction of liver dysfunction and survival

      TARE: prediction of liver dysfunction and survival

      Systemic therapy: prediction of liver dysfunction and survival

      Radiotherapy prediction of liver dysfunction and survival
      MELD scoreBilirubin, prothrombin time, creatinine, Na (∗)Estimation of global liver function and circulatory dysfunction (indirect)Surgery: prediction of liver failure and survival

      Liver transplantation: prediction of survival on waiting list
      ALBIAlbumin, bilirubinEstimation of global liver functionSurgical and non-surgical therapies: prediction of survival
      Indocyanine green clearanceRetention rate of indocyanine greenEstimation of liver functioning massSurgery: estimation of the extent of resection; prediction of liver dysfunction and survival
      LiMAx testAbility of the hepatocytes to metabolize the 13C-labelled-methacetinEstimation of liver functioning massSurgery: estimation of the extent of resection

      Locoregional therapy: prediction of liver dysfunction
      99Tc-mebrofenin scintigraphyMetabolism of 99Tc-mebrofeninEstimation of liver functioning massSurgery: estimation of the extent of resection; prediction of liver dysfunction
      99Tc-GSA scintigraphyThe ability of the hepatocyte to bind a synthetic asialoglycoproteinRegional distribution of the hepatic functionSurgery: estimation of the extent of resection; prediction of liver dysfunction

      Radiotherapy: estimation of the extent of the volume to be treated; prediction of liver dysfunction
      ElastographyLiver stiffnessEstimation of severity of liver fibrosisSurgery: prediction of liver dysfunction and survival

      Ablation: prediction of survival
      ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; TACE, transarterial chemoembolisation; TARE, transarterial radioembolisation.
      These include indocyanine green (ICG) clearance, a non-invasive indicator of hepatic blood flow that can be performed at the bedside in about 15-20 minutes. This test is unreliable in patients with bilirubin >3 mg/dl,
      • Vos J.J.
      • Wietasch J.K.G.
      • Absalom A.R.
      • Hendriks H.G.D.
      • Scheeren T.W.L.
      Green light for liver function monitoring using indocyanine green? An overview of current clinical applications.
      but such patients are usually not candidates for HCC treatments other than liver transplantation. ICG clearance is extensively used in the evaluation of patients before surgery and is able to predict postoperative liver dysfunction after hepatectomy.
      • Makuuchi M.
      • Kosuge T.
      • Takayama T.
      • Yamazaki S.
      • Kakazu T.
      • Miyagawa S.
      • et al.
      Surgery for small liver cancers.
      Similar to ICG clearance, the LiMAx test is based on the ability of hepatocytes to metabolise the 13C-labelled-methacetin by the cytochrome P4501A2 enzyme. The LiMAx test can be used as a surrogate method for the calculation of functional liver volume.
      • Stockmann M.
      • Lock J.F.
      • Riecke B.
      • Heyne K.
      • Martus P.
      • Fricke M.
      • et al.
      Prediction of postoperative outcome after hepatectomy with a new bedside test for maximal liver function capacity.
      Changes in LiMAx results have been observed after transarterial chemoembolisation (TACE) in patients with HCC.
      • Lock J.F.
      • Westphal T.
      • Rubin T.
      • Malinowski M.
      • Schulz A.
      • Jara M.
      • et al.
      LiMAx test improves diagnosis of chemotherapy-associated liver injury before resection of colorectal liver metastases.
      An inadequate assessment of liver functional reserve may not only lead to irreversible liver failure after a non-surgical treatment, but even in apparently mild instances it may prevent subsequent lines of therapy.
      Nuclear medicine may also be useful for the estimation of liver functional reserve, performing similarly to ICG, but obviously this cannot be obtained at the bedside and is scarcely utilised in the non-surgical settings and in Western countries.
      99Tc-IDA agent (99mTc-dimethyl-acetanilide-iminodiacetic acid) scintigraphy, for instance, enables the estimation of liver functional reserve based on the ability of these compounds to bind the anionic organic transporters of the hepatocytes and to be excreted into the bile canaliculi. Among these agents, the most used is the 99Tc-mebrofenin, which enables analysis of remnant liver function and prediction of liver dysfunction after surgery with a similar performance to ICG.
      • Erdogan D.
      • Heijnen B.
      • Bennink R.
      • Kok M.
      • Dinant S.
      • Straatsburg I.
      • et al.
      Preoperative assessment of liver function: a comparison of 99mTc-Mebrofenin scintigraphy with indocyanine green clearance test.
      ,
      • de Graaf W.
      • van Lienden K.P.
      • Dinant S.
      • JJTH Roelofs
      • Busch O.R.C.
      • Gouma D.J.
      • et al.
      Assessment of future remnant liver function using hepatobiliary scintigraphy in patients undergoing major liver resection.
      99Tc-GSA scintigraphy is another nuclear medicine technique that can be used to assess liver function, based on the ability of the hepatocyte to bind a synthetic asialoglycoprotein.
      • Kudo M.
      • Todo A.
      • Ikekubo K.
      • Hino M.
      • Yonekura Y.
      • Yamamoto K.
      • et al.
      Functional hepatic imaging with receptor-binding radiopharmaceutical: clinical potential as a measure of functioning hepatocyte mass.
      • Kudo M.
      • Todo A.
      • Ikekubo K.
      • Yamamoto K.
      • Vera D.R.
      • Stadalnik R.C.
      Quantitative assessment of hepatocellular function through in vivo radioreceptor imaging with technetium 99m galactosyl human serum albumin.
      • Imaeda T.
      • Kanematsu M.
      • Asada S.
      • Seki M.
      • Doi H.
      • Saji S.
      Utility of Tc-99m GSA SPECT imaging in estimation of functional volume of liver segments in health and liver diseases.
      In the non-surgical setting, it is increasingly being used to minimise the risk of radiation toxicity in the field of radiation therapy. In fact, thanks to the ability of 99TC-SPECT-CT and 99Tc-mebrofenin scintigraphy to detect not only global but also regional changes in liver function, it is possible to observe the impact of radioembolisation on liver functional reserve in treated and untreated liver regions.
      • Fernandez-Ros N.
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      • Paramo J.A.
      • Berasain C.
      • Avila M.A.
      • Chopitea A.
      • et al.
      Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation.
      • Allimant C.
      • Deshayes E.
      • Kafrouni M.
      • Santoro L.
      • de Verbizier D.
      • Fourcade M.
      • et al.
      Hepatobiliary scintigraphy and glass90y radioembolization with personalized dosimetry: dynamic changes in treated and nontreated liver.
      • Van Der Velden S.
      • Braat M.N.G.J.A.
      • Labeur T.A.
      • Scholten M.V.
      • Van Delden O.M.
      • Bennink R.J.
      • et al.
      A pilot study on hepatobiliary scintigraphy to monitor regional liver function in 90Y radioembolization.
      Liver stiffness can be easily measured, even at the bedside, with ultrasound-based methods
      • Dietrich C.F.
      • Bamber J.
      • Berzigotti A.
      • Bota S.
      • Cantisani V.
      • Castera L.
      • et al.
      EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, update 2017 (long version).
      and provides solid prognostic information in chronic liver disease. Its impact in HCC treatment selection has mainly been investigated in the setting of liver surgery, where it has shown prognostic value for the prediction of liver failure after hepatectomy and survival.
      • Cescon M.
      • Colecchia A.
      • Cucchetti A.
      • Peri E.
      • Montrone L.
      • Ercolani G.
      • et al.
      Value of transient elastography measured with FibroScan in predicting the outcome of hepatic resection for hepatocellular carcinoma.
      • Rajakannu M.
      • Cherqui D.
      • Ciacio O.
      • Golse N.
      • Pittau G.
      • Allard M.A.
      • et al.
      Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma.
      • Fung J.
      • Poon R.T.P.
      • Yu W.C.
      • Chan S.C.
      • Chan A.C.Y.
      • Chok K.S.H.
      • et al.
      Use of liver stiffness measurement for liver resection surgery: correlation with indocyanine green clearance testing and post-operative outcome.
      The potential role of liver stiffness measurement in identifying patients with poorer liver functional reserve and at higher risk of worse outcomes after non-surgical treatment procedures has only been shown by a preliminary report with ablation,
      • Lee P.C.
      • Chiou Y.Y.
      • Chiu N.C.
      • Chen P.H.
      • Liu C.A.
      • Kao W.Y.
      • et al.
      Liver stiffness measured by acoustic radiation force impulse elastography predicted prognoses of hepatocellular carcinoma after radiofrequency ablation.
      and should therefore be considered speculative.
      The next section will deal with expected outcomes after locoregional and systemic therapies in patients with different degrees of liver functional reserve.

      Importance of liver functional reserve for non-surgical treatment modalities

      Percutaneous tumour ablation

      Imaging-guided percutaneous ablation therapies such as radiofrequency or microwave ablation and percutaneous ethanol injection represent a potentially radical tumour treatment in early stage HCC that is only minimally invasive.
      • Kim Y.S.
      • Lim H.K.
      • Rhim H.
      • Lee M.W.
      Ablation of hepatocellular carcinoma.
      Radiofrequency ablation yielded a 3-year survival rate of up to 66% in patients with poorer liver functional reserve and a 5-year survival rate of up to 38% as a first-line treatment for patients with early stage HCC and Child-Pugh class B
      • Lencioni R.
      • Crocetti L.
      Local-regional treatment of hepatocellular carcinoma.
      • Yang W.
      • Yan K.
      • Goldberg S.N.
      • Ahmed M.
      • Lee J.C.
      • Wu W.
      • et al.
      Ten-year survival of hepatocellular carcinoma patients undergoing radiofrequency ablation as a first-line treatment.
      • Choi D.
      • Lim H.K.
      • Rhim H.
      • Kim Y.S.
      • Lee W.J.
      • Paik S.W.
      • et al.
      Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series.
      • Shiina S.
      • Tateishi R.
      • Arano T.
      • Uchino K.
      • Enooku K.
      • Nakagawa H.
      • et al.
      Radiofrequency ablation for hepatocellular carcinoma: 10-Year outcome and prognostic factors.
      (Table 2). As expected, given the same tumour bulk, patients with poorer liver functional reserve (e.g. Child-Pugh B vs. Child-Pugh A) have a worse prognosis under ablation treatment than patients with better liver function.
      • Lee D.H.
      • Lee J.M.
      • Lee J.Y.
      • Kim S.H.
      • Yoon J.H.
      • Kim Y.J.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma as first-line treatment: long-term results and prognostic factors in 162 patients with cirrhosis.
      • Sala M.
      • Llovet J.M.
      • Vilana R.
      • Bianchi L.
      • Solé M.
      • Ayuso C.
      • et al.
      Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.

      Lencioni R, Cioni D, Crocetti L, Franchini C, Pina C Della, Lera J, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology. 234(3):961–967.

      • Gardini A.C.
      • Marisi G.
      • Canale M.
      • Foschi F.G.
      • Donati G.
      • Ercolani G.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma: a meta-analysis of overall survival and recurrence-free survival.
      This is not only evident when using the Child-Pugh scoring system, but also when using the MELD score in compensated patients.
      The tools for the estimation of liver functional reserve include laboratory tests but also functional and imaging assays. Nuclear medicine allows for the estimation of regional liver reserve that may be useful for loco-regional treatment planning.
      Table 2Studies reporting long-term survival for patients with HCC treated with radiofrequency ablation as first-line treatment according to the Child-Turcotte-Pugh classification.
      StudyTumour featuresChild-Pugh class, nOverall survival (%)
      1-year follow-up3-year follow-up5-year follow-up
      Cammà et al. (2005)
      • Cammà C.
      • Di Marco V.
      • Orlando A.
      • Sandonato L.
      • Casaril A.
      • Parisi P.
      • et al.
      Treatment of hepatocellular carcinoma in compensated cirrhosis with radio-frequency thermal ablation (RFTA): a prospective study.
      Single tumour ≤5 cm; up to 3 tumours ≤3 cmA (n = 165)83%59%
      at 30 months.
      NR
      B (n = 37)66%48%
      at 30 months.
      NR
      Lencioni et al. (2005)
      • Lencioni R.
      • Cioni D.
      • Crocetti L.
      • Franchini C.
      • Pina C Della
      • Lera J.
      • et al.
      Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.
      Single tumour ≤5 cm; up to 3 tumours ≤3 cmA (n = 144)100%76%51%
      B (n = 43)89%46%31%
      Tateishi et al. (2005)
      • Tateishi R.
      • Shiina S.
      • Teratani T.
      • Obi S.
      • Sato S.
      • Koike Y.
      • et al.
      Percutaneous radiofrequency ablation for hepatocellular carcinoma: an analysis of 1000 cases.
      Number/size inclusion criteria not specifiedA (n = 221)96%83%63%
      B–C
      Only 4 out of 98 patients had Child-Pugh C cirrhosis.
      (n = 98)
      90%65%31%
      Choi et al. (2007)
      • Choi D.
      • Lim H.K.
      • Rhim H.
      • Kim Y.S.
      • Lee W.J.
      • Paik S.W.
      • et al.
      Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series.
      Single tumour ≤5 cm; up to 3 tumours ≤3 cmA (n = 359)NR78%64%
      B (n = 160)49%38%
      Yan et al. (2008)
      • Yan K.
      • Chen M.H.
      • Yang W.
      • Wang Y Bin
      • Gao W.
      • Hao C.Y.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma: long-term outcome and prognostic factors.
      Tumour size ≤7 cm, tumour number ≤5A (n = 160)89.7%73.4%62.8%
      B (n = 94)77.2%39.9%27%
      C (n = 12)58.3%25%25%
      Wakuta et al. (2011)
      • Wakuta A.
      • Nouso K.
      • Kariyama K.
      • Nishimura M.
      • Kishida M.
      • Wada N.
      • et al.
      Radiofrequency ablation for the treatment of hepatocellular carcinoma with decompensated cirrhosis.
      Single tumour ≤5 cm; up to 3 tumours ≤3 cmB (n = 56)82%47%NR
      C (n = 10)83%31%NR
      Shiina et al. (2012)
      • Shiina S.
      • Tateishi R.
      • Arano T.
      • Uchino K.
      • Enooku K.
      • Nakagawa H.
      • et al.
      Radiofrequency ablation for hepatocellular carcinoma: 10-Year outcome and prognostic factors.
      Single tumour ≤5 cm in diameter; up to 3 tumours ≤3 cmA (n = 868)98%86%65.9%
      B (n = 291)93.2%66.4%46.5%
      C (n = 11)81.8%58.4%23.4%
      Yang et al. (2016)
      • Kim Y.S.
      • Lim H.K.
      • Rhim H.
      • Lee M.W.
      Ablation of hepatocellular carcinoma.
      Single tumour ≤5 cm; up to 3 tumours ≤3 cmA (n = 250)94.1%78.9%60.1%
      B (n = 57)82.5%46.8%25.9%
      C (n = 9)28.6%14.3%0%
      NR, not reported.
      Only 4 out of 98 patients had Child-Pugh C cirrhosis.
      ^ at 30 months.
      For instance, for a tumour size of 3 cm, median survival was estimated to be 4.25 years in patients with an MELD score of 7-8, 4.05 years for MELD 9-10 and 3.85 years for MELD 11-12, respectively.
      • Cucchetti A.
      • Piscaglia F.
      • Cescon M.
      • Serra C.
      • Colecchia A.
      • Maroni L.
      • et al.
      An explorative data-analysis to support the choice between hepatic resection and radiofrequency ablation in the treatment of hepatocellular carcinoma.
      Such a homogeneously progressive, but limited, decrease in survival with slightly increasing MELD scores tends to suggest that ablation itself has an extremely limited impact on worsening liver function; thus, it is not expected to prevent the possibility of subsequent lines of therapy in compensated patients. The occurrence of liver decompensation after thermal ablation is in fact extremely low. Similar expectations would not apply to surgical resection. Hypothetically, progressing MELD scores would in fact produce a sharper survival drop with surgery than ablation for an identical tumour,
      • 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.
      suggesting that surgery has a heavier impact on the liver functional reserve than ablation. Therefore, the risk and benefits of an approach must be carefully balanced when choosing curative treatments in patients with partially compromised liver function, to ensure that patients can still receive subsequent lines of therapy in the instance of tumour relapse. Regarding the choice of ablation vs. TACE, it must be considered that the latter is usually indicated for greater tumour bulks, limiting the availability of comparative information on liver function deterioration.
      Briefly, suboptimal liver function, e.g. Child-Pugh B, cannot per se be considered a contraindication to ablation. The choice of whether to offer locoregional therapies or best supportive care (since systemic treatments are still not validated in this patient segment) to patients with Child-Pugh B cirrhosis must be individualised.
      To date, almost no studies have specifically investigated whether the risk of occurrence of post-procedure complications differs between patients with Child-Pugh A or B cirrhosis. An increase in the Child-Pugh score after thermoablation was reported in 3-7% of patients with Child-Pugh A and 3-14% of those with Child-Pugh B cirrhosis.
      • Giorgio A.
      • Merola M.G.
      • Montesarchio L.
      • Merola F.
      • Gatti P.
      • Coppola C.
      • et al.
      Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years.
      • Wakuta A.
      • Nouso K.
      • Kariyama K.
      • Nishimura M.
      • Kishida M.
      • Wada N.
      • et al.
      Radiofrequency ablation for the treatment of hepatocellular carcinoma with decompensated cirrhosis.
      • Koike Y.
      • Yoshida H.
      • Shiina S.
      • Teratani T.
      • Obi S.
      • Sato S.
      • et al.
      Changes in hepatic functional reserve after percutaneous tumor ablation for hepatocellular carcinoma: long-term follow up for 227 consecutive patients with a single lesion.
      Finally, it is worth noting that ascites and/or uncorrectable coagulopathy, usually found in patients with decompensated Child-Pugh B or C cirrhosis, remain contraindications to percutaneous ablation because, on the one hand, they are associated with a higher risk of bleeding and, on the other hand, prognosis is usually determined by the degree of liver dysfunction in this situation rather than by the limited tumour burden expected for lesions amenable to ablation.

      Transarterial chemoembolisation

      Compared to resection or ablation, TACE is an effective treatment for a broader range of tumour burdens, spanning from small single unresectable HCC that cannot be treated with ablation due to technical issues, to intermediate-stage large multinodular HCC. Additionally, TACE represents a heterogeneous method from the technical point of view, since it can be performed with variable angiographic approaches (lobar, selective or superselective), with different or no chemotherapy drugs, and with different embolising agents, including new drug-eluting beads
      • Raoul J.L.
      • Sangro B.
      • Forner A.
      • Mazzaferro V.
      • Piscaglia F.
      • Bolondi L.
      • et al.
      Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization.
      ; all these technical variants might have different short- and long-term effects on liver function, theoretically related to the extent, severity and duration of parenchymal ischaemia. The combination of the aforementioned factors is expected to variably affect the number and size of downstream occluded arteries, as well as the duration and extent of microvascular obstruction: complete vs. incomplete, or temporary (days/weeks) vs. permanent. Additionally, it has not been demonstrated whether different chemotherapeutic agents induce different local damaging effects.
      Uncertainties in assessing the effects of different technical approaches also relate to the fact that assessing the effect of TACE on liver function is difficult, since median values are often unchanged, with only a limited proportion of patients suffering deterioration. This is why clinically meaningful thresholds of worsening in laboratory values after TACE were recently designed and tested.
      • Miksad R.A.
      • Ogasawara S.
      • Xia F.
      • Fellous M.
      • Piscaglia F.
      Liver function changes after transarterial chemoembolization in US hepatocellular carcinoma patients: the LiverT study.
      For instance, total bilirubin was marginally increased in a real-life American population at 3 months after TACE, passing from a median (range) of 1.2 mg/dl (0.09–6.9) to a similar value of 1.2 mg/dl (0.2–41.3) (p <0.01). However, considering the clinically meaningful thresholds of either an increase in bilirubin of ≥50% or bilirubin values >3 mg/dl in the chronic period after TACE, rather than median values, levels above the threshold were observed in 23% and in 26.5% of patients for each definition, respectively.
      • Giorgio A.
      • Merola M.G.
      • Montesarchio L.
      • Merola F.
      • Gatti P.
      • Coppola C.
      • et al.
      Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years.
      Similar findings were shown for albumin and INR.
      • Giorgio A.
      • Merola M.G.
      • Montesarchio L.
      • Merola F.
      • Gatti P.
      • Coppola C.
      • et al.
      Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years.
      The clinical consequence of such real-life data is that a non-negligible proportion of patients submitted to TACE (not precisely defined, but that could be roughly estimated as 10–20% of patients in real life, based on a real-life American population)
      • Giorgio A.
      • Merola M.G.
      • Montesarchio L.
      • Merola F.
      • Gatti P.
      • Coppola C.
      • et al.
      Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years.
      would experience a (subclinical) worsening of liver function and potentially no longer be candidates for systemic therapies.
      Definitive conclusions on the use of TACE in patients with worse liver functional reserve are difficult to reach because there is a wide variability in tumour burden as well as in TACE protocols. Most of the patients enrolled in randomised studies of TACE vs. best supportive care had Child-Pugh class A cirrhosis. Therefore, it was not possible to produce any definitive evidence of the survival efficacy of TACE in patients with Child-Pugh class B,
      • Raoul J.L.
      • Sangro B.
      • Forner A.
      • Mazzaferro V.
      • Piscaglia F.
      • Bolondi L.
      • et al.
      Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization.
      ,
      • Facciorusso A.
      • Licinio R.
      • Muscatiello N.
      • Di Leo A.
      • Barone M.
      Transarterial chemoembolization: evidences from the literature and applications in hepatocellular carcinoma patients.
      since no direct comparison with supportive care or alternative effective therapies is available in this patient segment.
      Local ablation therapies may be applied in patients with a fairly preserved liver function. Under standard conditions and indications, these therapies usually have a scarce impact on liver functional reserve.
      In keeping with these data, patients with Child-Pugh C cirrhosis are excluded from TACE in all guidelines, whereas those with Child-Pugh B are variably considered as TACE candidates: some national and continental guidelines accept selected compensated patients with Child-Pugh B, whereas others exclude all such cases.
      • Galle P.R.
      • Forner A.
      • Llovet J.M.
      • Mazzaferro V.
      • Piscaglia F.
      • Raoul J.L.
      • et al.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Takayasu K.
      • Arii S.
      • Kudo M.
      • Ichida T.
      • Matsui O.
      • Izumi N.
      • et al.
      Superselective transarterial chemoembolization for hepatocellular carcinoma. Validation of treatment algorithm proposed by Japanese guidelines.
      • Benson A.B.
      • Abrams T.A.
      • Ben-Josef E.
      • Bloomston P.M.
      • Botha J.F.
      • Clary B.M.
      • et al.
      NCCN clinical practice guidelines in oncology: hepatobiliary cancers.
      • Lammer J.
      • Malagari K.
      • Vogl T.
      • Pilleul F.
      • Denys A.
      • Watkinson A.
      • et al.
      Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION v study.
      At present these patients are also not candidates for systemic therapies.
      Regarding the use of drug-eluting beads, current guidelines agree that further confirmation is needed before expanding the subset of patients with Child-Pugh B cirrhosis for whom TACE could be considered; despite reports of better objective tumour responses, no detailed information
      • Lammer J.
      • Malagari K.
      • Vogl T.
      • Pilleul F.
      • Denys A.
      • Watkinson A.
      • et al.
      Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION v study.
      nor any demonstration
      • Golfieri R.
      • Giampalma E.
      • Renzulli M.
      • Cioni R.
      • Bargellini I.
      • Bartolozzi C.
      • et al.
      Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.
      that this translated into longer overall survival was provided.
      In consideration of the concurrent role of tumour bulk and liver functional reserve on outcome, a group of experts attempted to propose a sub-classification of the Barcelona Clinic liver cancer (BCLC) staging system
      • Bolondi L.
      • Burroughs A.
      • Dufour J.F.
      • Galle P.R.
      • Mazzaferro V.
      • Piscaglia F.
      • et al.
      Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions.
      to account for both aspects. The so-called "up-to-seven" criteria were utilised as a rough measure of tumour bulk
      • Bolondi L.
      • Burroughs A.
      • Dufour J.F.
      • Galle P.R.
      • Mazzaferro V.
      • Piscaglia F.
      • et al.
      Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions.
      ,
      • Mazzaferro V.
      • Llovet J.M.
      • Miceli R.
      • Bhoori S.
      • Schiavo M.
      • Mariani L.
      • et al.
      Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.
      and, for Child-Pugh class B, individual Child-Pugh scores rather than the entire class were used to assess liver functional reserve, resulting in 4 intermediate BCLC-B stage subclasses, with different priorities in treatment allocation
      • Bolondi L.
      • Burroughs A.
      • Dufour J.F.
      • Galle P.R.
      • Mazzaferro V.
      • Piscaglia F.
      • et al.
      Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions.
      and progressively shorter expected survival (from B1 to B4). Besides this proposal, several other prognostic models have been proposed to try to take into account all of these factors, to predict patient survival and to guide the initiation or repetition of TACE (Table 3),
      • Kadalayil L.
      • Benini R.
      • Pallan L.
      • O’Beirne J.
      • Marelli L.
      • Yu D.
      • et al.
      A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.
      • Pinato D.J.
      • Arizumi T.
      • Allara E.
      • Jang J.W.
      • Smirne C.
      • Kim Y.W.
      • et al.
      Validation of the hepatoma arterial embolization PrognosticScore in European and asian populations and proposed modification.
      • Park Y.
      • Kim S.U.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • Ahn S.H.
      • et al.
      Addition of tumor multiplicity improves the prognostic performance of the hepatoma arterial-embolization prognostic score.
      • Cappelli A.
      • Cucchetti A.
      • Cabibbo G.
      • Mosconi C.
      • Maida M.
      • Attardo S.
      • et al.
      Refining prognosis after trans-arterial chemo-embolization for hepatocellular carcinoma.
      • Sieghart W.
      • Hucke F.
      • Pinter M.
      • Graziadei I.
      • Vogel W.
      • Müller C.
      • et al.
      The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma.
      • Hucke F.
      • Pinter M.
      • Graziadei I.
      • Bota S.
      • Vogel W.
      • Müller C.
      • et al.
      How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.
      • Adhoute X.
      • Penaranda G.
      • Naude S.
      • Raoul J.L.
      • Perrier H.
      • Bayle O.
      • et al.
      Retreatment with TACE: the ABCR SCORE, an aid to the decision-making process.
      • Nam J.Y.
      • Choe A.R.
      • Sinn D.H.
      • Lee J.H.
      • Kim H.Y.
      • Yu S.J.
      • et al.
      A differential risk assessment and decision model for Transarterial chemoembolization in hepatocellular carcinoma based on hepatic function.
      • Han G.
      • Berhane S.
      • Toyoda H.
      • Bettinger D.
      • Elshaarawy O.
      • Chan A.W.H.
      • et al.
      Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach.
      but none have been widely adopted so far (Table 3).
      Table 3Overview of clinical scoring systems to improve patient selection for TACE.
      ScoreVariables
      Variables with independent prognostic role on overall survival.
      HAP (2013)
      • Kadalayil L.
      • Benini R.
      • Pallan L.
      • O’Beirne J.
      • Marelli L.
      • Yu D.
      • et al.
      A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.
      Albumin <36 g/dl, alpha-fetoprotein >400 ng/ml, bilirubin >17 μmol/L, max tumour diameter >7 cm
      mHAP (2015)
      • Pinato D.J.
      • Arizumi T.
      • Allara E.
      • Jang J.W.
      • Smirne C.
      • Kim Y.W.
      • et al.
      Validation of the hepatoma arterial embolization PrognosticScore in European and asian populations and proposed modification.
      Tumour size (>7 cm), alpha-fetoprotein (>400 ng/ml), serum albumin (<3.6 g/dl)
      mHAP-II (2015)
      • Park Y.
      • Kim S.U.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • Ahn S.H.
      • et al.
      Addition of tumor multiplicity improves the prognostic performance of the hepatoma arterial-embolization prognostic score.
      Tumour size (>7 cm), tumour number (≥2), alpha-fetoprotein (>400 ng/ml), total bilirubin (>0.9 mg/dl), serum albumin (<3.6 g/dl)
      mHAP-III (2016)
      • Cappelli A.
      • Cucchetti A.
      • Cabibbo G.
      • Mosconi C.
      • Maida M.
      • Attardo S.
      • et al.
      Refining prognosis after trans-arterial chemo-embolization for hepatocellular carcinoma.
      Maximum tumour size (cm), tumour number, alpha-fetoprotein (ng/ml), albumin (g/dl), bilirubin (mg/dl)
      ART (2013)
      • Sieghart W.
      • Hucke F.
      • Pinter M.
      • Graziadei I.
      • Vogel W.
      • Müller C.
      • et al.
      The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma.
      AST increase >25% (present vs. absent), Child-Pugh score increase (1-point vs. ≥2 points vs. absent), radiological tumour response (present vs. absent)
      STATE (2014)
      • Hucke F.
      • Pinter M.
      • Graziadei I.
      • Bota S.
      • Vogel W.
      • Müller C.
      • et al.
      How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.
      Albumin levels (g/L), up-to-7 criteria (out vs. in), C-reactive protein levels ≥1 mg/dl
      START Strategy (2014)
      • Hucke F.
      • Pinter M.
      • Graziadei I.
      • Bota S.
      • Vogel W.
      • Müller C.
      • et al.
      How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.
      Sequential use of the STATE and the ART-score improves TACE outcomes
      ABCR (2015)
      • Adhoute X.
      • Penaranda G.
      • Naude S.
      • Raoul J.L.
      • Perrier H.
      • Bayle O.
      • et al.
      Retreatment with TACE: the ABCR SCORE, an aid to the decision-making process.
      BCLC, alpha-fetoprotein (>200 ng/ml), increase in Child-Pugh score by P2, absence of radiological response
      TACE-Predict (2019):
      • Han G.
      • Berhane S.
      • Toyoda H.
      Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach.
      • -
        Pre-TACE-Predict
      • -
        Post-TACE-Predict
      Tumour number, tumour size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause of liver disease, Baseline (Pre-TACE) variables + mRECIST response
      ASAR (2020)
      • Nam J.Y.
      • Choe A.R.
      • Sinn D.H.
      • Lee J.H.
      • Kim H.Y.
      • Yu S.J.
      • et al.
      A differential risk assessment and decision model for Transarterial chemoembolization in hepatocellular carcinoma based on hepatic function.
      ALBI grade, maximal tumour size, alpha-fetoprotein, tumour response to initial TACE
      ABCR, alpha-fetoprotein, BCLC, Child-Pugh, and Response; ALBI, albumin-bilirubin; ART, assessment for retreatment with TACE; ASAR, ALBI-size-alpha-fetoprotein-response; AST, aspartate aminotransferase; BCLC, Barcelona Clinic liver cancer; HAP, hepatoma arterial embolisation prognostic score; mHAP, modified HAP score; STATE, selection for transarterial chemoembolisation treatment; TACE, transarterial chemoembolisation.
      Variables with independent prognostic role on overall survival.
      As briefly alluded to, one critical issue is also the decision to withdraw patients who did not achieve complete response after a previous TACE, since up to one-third of patients are reported to suffer from clinically meaningful deterioration of liver function after one session of TACE in real life. Patients in whom a previous TACE induced a clinical decompensation are no longer candidates for TACE retreatment. In such cases, systemic therapy should be considered if the patient recovers sufficiently, or otherwise best non-oncologic care. Some patients instead suffer a worsening of liver function parameters after TACE, without reaching a decompensated stage; in this instance, the severity of the liver function worsening is related to a poorer prognosis after a second TACE treatment. Scores were proposed to try to identify suitable candidates for TACE retreatment in this setting, also considering changes in functional liver variables before and after TACE. Such scores, however, were mainly designed to stratify candidates by anticipated survival, similarly to those designed for the first TACE, whereas large studies specifically analysing the effect of repeated TACE on liver functional reserve are still lacking. A further deterioration of liver function (assessed as MELD, ALBI, Child-Pugh or clinically – based on changes in individual laboratory variables, such as bilirubin, albumin or INR, or the appearance of subclinical ascites) should nonetheless be reasonably expected if deterioration occurred after a first TACE. Therefore, the decision to repeat TACE must be made much more cautiously. In fact, the occurrence of liver function deterioration, even subclinical, after TACE may lead to the transition from Child-Pugh class A to B cirrhosis. Such worsening may consequently prevent the patient from receiving effective first-line systemic therapies or, if not preventing first-line therapy, may nonetheless make the liver more prone to further deterioration and prevent the patient from undergoing future lines of systemic treatment (second or third line), which is more clinically relevant now that new approaches are more frequently associated with a complete tumour response.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      ,
      • 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.
      • 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.
      ,
      • 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.
      ,
      • Kudo M.
      • Matilla A.
      • Santoro A.
      • Melero I.
      • Gracián A.C.
      • Acosta-Rivera M.
      • et al.
      CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.
      To this end, no scoring system has been able to identify the best option for any individual patient within the segment of patients with suboptimal liver functional reserve. The choice still depends mainly upon the opinion of experts, who must include the hepatologist who visited the patient and is familiar with his/her liver functional reserve, clinical history and the extent of expected residual embolisation to be carried out.
      TACE is generally considered only for patients with compensated liver disease and is indicated for the widest range of candidates. Considering the entire spectrum of possible post-TACE liver damage, some deterioration of liver function is not uncommon after TACE, especially in patients with large tumour burden and suboptimal baseline liver functional reserve. Great attention must therefore be paid when proceeding to the first or subsequent sessions, in order to avoid a deterioration in liver function. In fact, even a subclinical deterioration, not yet leading to frank decompensation, may nonetheless prevent subsequent systemic therapy.

      Transarterial radioembolisation

      Transarterial radioembolisation (TARE) is a form of brachytherapy in which radionuclide-loaded particles are injected into the tumour vascular bed through the hepatic artery. Three types of radiolabelled microspheres are commercially available, Yttrium 90 (Y90)-resin spheres (SIR-Sphere®), Y90-glass spheres (TheraSphereTM) and Ho-166poly-L-lactic acid (PLLA) microspheres (QuiremSpheres®). The most used in the clinical setting are the Y90-loaded spheres. The smaller size of the particles used in TARE compared with particles used in TACE (35 microns vs. 100-500 microns) is an advantage because the antitumoural effect is due to the radiation released by the Y90-loaded spheres and significant embolic effects are mostly prevented. However, liver toxicity after TARE, called REILD (radioembolisation-induced liver disease), exists and depends on the dose of radiation that reaches the non-tumoural parenchyma and the pre-existing degree of liver dysfunction. REILD is a well-defined syndrome characterised by the appearance of jaundice and ascites 4-8 weeks after TARE in the absence of tumour progression or bile duct occlusion.
      • Sangro B.
      • Gil-Alzugaray B.
      • Rodriguez J.
      • Sola I.
      • Martinez-Cuesta A.
      • Viudez A.
      • et al.
      Liver disease induced by radioembolization of liver tumors: description and possible risk factors.
      It is most common in patients who previously received chemotherapy in an extensive, up to whole-liver, treatment strategy and in patients with cirrhosis or reduced liver functional reserve. A total liver volume smaller than 1.5 L and a total bilirubin serum level higher than 1.2 mg/dl are the main identified risk factors for REILD in patients with cirrhosis.
      • Gil-Alzugaray B.
      • Chopitea A.
      • Iñarrairaegui M.
      • Bilbao J.I.
      • Rodriguez-Fraile M.
      • Rodriguez J.
      • et al.
      Prognostic factors and prevention of radioembolization-induced liver disease.
      Indeed, severe to moderate clinically detectable ascites or bilirubin levels >1.5-2.0 mg/dl indicate an insufficient pre-treatment functional reserve
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after Yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A El
      • Scherag A.
      • MüLler S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      and are contraindications for TARE. The presence of ascites detected only by CT scan or ultrasound and subsequently treated successfully with diuretics could be an exception.
      Besides REILD, a worsening of liver function after TARE has been reported in approximately 10–20% of patients, occurring independently of tumour stage
      • Mazzaferro V.
      • Sposito C.
      • Bhoori S.
      • Romito R.
      • Chiesa C.
      • Morosi C.
      • et al.
      Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.
      ,
      • Gramenzi A.
      • Golfieri R.
      • Mosconi C.
      • Cappelli A.
      • Granito A.
      • Cucchetti A.
      • et al.
      Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.
      and mainly involving an any grade increase in bilirubin and alkaline phosphatase, a decrease in albumin, an increase in Child-Pugh score and/or hepatic decompensation.
      • Mazzaferro V.
      • Sposito C.
      • Bhoori S.
      • Romito R.
      • Chiesa C.
      • Morosi C.
      • et al.
      Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.
      • Gramenzi A.
      • Golfieri R.
      • Mosconi C.
      • Cappelli A.
      • Granito A.
      • Cucchetti A.
      • et al.
      Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.
      • Salem R.
      • Gabr A.
      • Riaz A.
      • Mora R.
      • Ali R.
      • Abecassis M.
      • et al.
      Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience.
      Recent observations from a sub-study of the SORAMIC trial, in which a stronger increase of ALBI score after TARE was observed in patients older than 65, patients with cirrhosis, those with a Child-Pugh score >5 and those previously treated with TACE, suggest that pre-treatment liver functional reserve and indeed the regenerative ability of the liver determine the risk of liver dysfunction after TARE.
      • Ricke J.
      • Schinner R.
      • Seidensticker M.
      • Gasbarrini A.
      • van Delden O.M.
      • Amthauer H.
      • et al.
      Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma.
      However, whether this prevents patients from receiving a subsequent treatment has not yet been extensively investigated.
      • Memon K.
      • Kulik L.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Benson A.B.
      • Ganger D.
      • et al.
      Radioembolization for hepatocellular carcinoma with portal vein thrombosis: impact of liver function on systemic treatment options at disease progression.
      Regarding combination therapy, a greater deterioration in liver function was observed in patients with baseline ALBI grade ≥2 vs. 1 in a multicentre study testing TARE plus nivolumab.
      • de la Torre-Aláez M.
      • Matilla A.
      • Varela M.
      • Iñarrairaegui M.
      • Reig M.
      • JL L.
      • et al.
      Preliminary analysis of early liver adverse events (LAE) in patients with hepatocellular carcinoma treated with selective internal radiation therapy (SIRT) and nivolumab.
      Similarly, patients treated with TARE in combination with sorafenib seem to be more prone to develop hyperbilirubinemia and fatigue compared to patients treated with sorafenib alone. The combination of sorafenib with TARE was reported to confer some benefit in a subgroup of patients from the SORAMIC trial, who were speculated to tolerate TARE better due to a larger liver functional reserve (namely patients without cirrhosis, those with Child-Pugh A not B, and those who had not received any previous TACE).
      • Ricke Jens
      • Klümpen H.J.
      • Amthauer H.
      • Bargellini I.
      • Bartenstein P.
      • Toni EN de
      • et al.
      Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.
      In addition to changes in liver function tests, an increase in spleen volume, described in patients treated in both liver lobes, and an increase in liver stiffness mainly in the tumoral and peritumoral liver after TARE, may suggest that liver fibrosis induced by radiation could potentially increase portal hypertension.
      • Jakobs T.F.
      • Saleem S.
      • Atassi B.
      • Reda E.
      • Lewandowski R.J.
      • Yaghmai V.
      • et al.
      Fibrosis, portal hypertension, and hepatic volume changes induced by intra-arterial radiotherapy with 90Yttrium microspheres.
      ,
      • Kennedy P.
      • Lewis S.
      • Bane O.
      • Hectors S.J.
      • Kim E.
      • Schwartz M.
      • et al.
      Early effect of 90Y radioembolisation on hepatocellular carcinoma and liver parenchyma stiffness measured with MR elastography: initial experience.
      However, the risk of variceal bleeding did not appear to be significantly increased in a large series of patients treated with TARE. Finally, liver scintigraphy demonstrated a regional change in function after TARE in several series of patients with HCC. The real meaning of these findings for liver functional reserve and the tolerability of sequential treatments is not known.
      Regarding the impact of liver reserve on prognosis, baseline liver function indicators (bilirubin, albumin, ascites and Child-Pugh) have an independent predictive value on survival after TARE as expected, either when considered alone
      • Salem R.
      • Gabr A.
      • Riaz A.
      • Mora R.
      • Ali R.
      • Abecassis M.
      • et al.
      Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience.
      or combined in the ALBI score
      • Antkowiak M.
      • Gabr A.
      • Das A.
      • Ali R.
      • Kulik L.
      • Ganger D.
      • et al.
      Prognostic role of albumin, bilirubin, and ALBI scores: analysis of 1000 patients with hepatocellular carcinoma undergoing radioembolization.
      ,
      • Mohammadi H.
      • Abuodeh Y.
      • Jin W.
      • Frakes J.
      • Friedman M.
      • Biebel B.
      • et al.
      Using the Albumin-Bilirubin (ALBI) grade as a prognostic marker for radioembolization of hepatocellular carcinoma.
      (Table 4).
      TARE is considered a safe choice for patients with large tumours with preserved liver function. A worsening of liver function tests may be observed after TARE and is usually associated with poor pre-treatment liver function, a smaller total liver volume and a higher dose of radiation. However, to what extent this may impede the deliver of subsequent treatments remains unclear.
      Table 4Predictive factors of toxicity and survival in patients treated with external radiotherapy and TARE.
      ToxicityStudySurvivalStudy
      External radiotherapy
      ALBI score>1Murray et al. 2018
      • Murray L.J.
      • Sykes J.
      • Brierley J.
      • Kim J.J.
      • Wong R.K.S.
      • Ringash J.
      • et al.
      Baseline albumin-bilirubin (ALBI) score in western patients with hepatocellular carcinoma treated with stereotactic body radiation therapy (SBRT).
      >1Murray et al. 2018;
      • Garin E.
      • Palard X.
      • Rolland Y.
      Personalised dosimetry in radioembolisation for HCC: impact on clinical outcome and on trial design.
      Su et al. 2019
      • Su T.S.
      • Yang H.M.
      • Zhou Y.
      • Huang Y.
      • Liang P.
      • Cheng T.
      • et al.
      Albumin - bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy.
      Child-Pugh score≥6Murray et al. 2018
      • Murray L.J.
      • Sykes J.
      • Brierley J.
      • Kim J.J.
      • Wong R.K.S.
      • Ringash J.
      • et al.
      Baseline albumin-bilirubin (ALBI) score in western patients with hepatocellular carcinoma treated with stereotactic body radiation therapy (SBRT).
      A5 vs. A6

      A vs. B
      Murray et al. 2018;
      • Garin E.
      • Palard X.
      • Rolland Y.
      Personalised dosimetry in radioembolisation for HCC: impact on clinical outcome and on trial design.
      Su et al. 2019
      • Su T.S.
      • Yang H.M.
      • Zhou Y.
      • Huang Y.
      • Liang P.
      • Cheng T.
      • et al.
      Albumin - bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy.
      Residual functional volume<700 mlGuha et al. 2011
      • Guha C.
      • Kavanagh B.D.
      Hepatic radiation toxicity: avoidance and amelioration.
      HBV statusHBV+ vs. HBV-Cheng et al. 2004
      • Cheng J.C.H.
      • Wu J.K.
      • Lee P.C.T.
      • Liu H.S.
      • Jian J.J.M.
      • Lin Y.M.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      TARE
      ALBI score≥2De la Torre-Aláez et al. 2019
      • de la Torre-Aláez M.
      • Matilla A.
      • Varela M.
      • Iñarrairaegui M.
      • Reig M.
      • JL L.
      • et al.
      Preliminary analysis of early liver adverse events (LAE) in patients with hepatocellular carcinoma treated with selective internal radiation therapy (SIRT) and nivolumab.
      ≥2Antkowiak et al. 2019;
      • Antkowiak M.
      • Gabr A.
      • Das A.
      • Ali R.
      • Kulik L.
      • Ganger D.
      • et al.
      Prognostic role of albumin, bilirubin, and ALBI scores: analysis of 1000 patients with hepatocellular carcinoma undergoing radioembolization.
      Mohammadi et al. 2018
      • Mohammadi H.
      • Abuodeh Y.
      • Jin W.
      • Frakes J.
      • Friedman M.
      • Biebel B.
      • et al.
      Using the Albumin-Bilirubin (ALBI) grade as a prognostic marker for radioembolization of hepatocellular carcinoma.
      Bilirubin>1.2 mg/dlGil-Alzugaray et al. 2013
      • Gil-Alzugaray B.
      • Chopitea A.
      • Iñarrairaegui M.
      • Bilbao J.I.
      • Rodriguez-Fraile M.
      • Rodriguez J.
      • et al.
      Prognostic factors and prevention of radioembolization-induced liver disease.
      Child-Pugh scoreAA vs. BHilgard et al. 2010
      • Hilgard P.
      • Hamami M.
      • Fouly A El
      • Scherag A.
      • MüLler S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      Residual liver volume1,500 mlGil-Alzugaray et al. 2013
      • Gil-Alzugaray B.
      • Chopitea A.
      • Iñarrairaegui M.
      • Bilbao J.I.
      • Rodriguez-Fraile M.
      • Rodriguez J.
      • et al.
      Prognostic factors and prevention of radioembolization-induced liver disease.
      ALBI, albumin-bilirubin; TARE, transarterial radioembolisation.
      It is worth remembering, however, that the pivotal phase III trials comparing TARE to sorafenib in locally advanced HCC failed to meet their primary objective of superior overall survival.
      • Vilgrain V.
      • Pereira H.
      • Assenat E.
      • Guiu B.
      • Ilonca A.D.
      • Pageaux G.P.
      • et al.
      Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.
      ,
      • Chow P.K.H.
      • Gandhi M.
      • Tan S.B.
      • Khin M.W.
      • Khasbazar A.
      • Ong J.
      • et al.
      SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.
      Consequently, patients offered a different option (i.e. TARE) from the reference standard (systemic therapy) in the setting of locally advanced cases must be highly selected not only in terms of tumour load, but also liver functional reserve (which must be very good), and at best they should be included within experimental studies. Specifically, patients should be within Child-Pugh class A and have an ALBI grade of 1,
      • Palmer D.H.
      • Hawkins N.S.
      • Vilgrain V.
      • Pereira H.
      • Chatellier G.
      • Ross P.J.
      Tumor burden and liver function in HCC patient selection for selective internal radiation therapy: SARAH post-hoc study.
      to avoid the risk of liver decompensation or even of a worsening of liver function that might prevent the patient from receiving different lines of effective systemic therapies if needed. The regular use of dosimetry prior to Y90 delivery appears to be another tool to improve efficacy and reduce liver damage,
      • Garin E.
      • Palard X.
      • Rolland Y.
      Personalised dosimetry in radioembolisation for HCC: impact on clinical outcome and on trial design.
      but whether this can be used to expand the pool of candidates is yet to be proven.

      Systemic therapies

      All systemic therapies currently approved for the treatment of HCC have been tested almost exclusively in patients with Child-Pugh class A cirrhosis. There is little data available about the safety profile and efficacy of these therapies in patients with significant liver dysfunction.
      The drug that has accumulated the largest evidence base in patients with HCC and more compromised liver function is sorafenib, approved in 2007 as the first-line systemic therapy for HCC. A large real-life multicentric study analysing patients treated with sorafenib, confirmed that liver functional reserve has an obvious prognostic and linear impact on survival. The overall survival of patients with Child-Pugh A cirrhosis (13.6 months, [95% CI 12.8-14.7]) was considerably longer than for Child-Pugh B (5.2 months [95% CI 4.6-6.3]) or C (2.6 months [95% CI 1.5-4.0]); within the Child-Pugh B class there is a progressive decrease in survival from Child-Pugh B7 (6.2 months [95% CI 4.9-8.7]) to B8 (4.8 months [95% CI 4.1-6.9]) and to B9 (3.7 months [95% CI 3.0-5.1]).
      • 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.
      Another European study suggested that more advanced liver dysfunction (Child-Pugh B ≥9 vs. <9) not only predicts shorter overall survival, but also a significantly shorter time to progression.
      • Ganten T.M.
      • Stauber R.E.
      • Schott E.
      • Malfertheiner P.
      • Buder R.
      • Galle P.R.
      • et al.
      Sorafenib in patients with hepatocellular carcinoma—results of the observational INSIGHT study.
      Regarding safety and tolerability, severe adverse events and treatment interruption due to adverse effects were more common in patients with Child-Pugh class B vs. Child-Pugh A (60% vs. 36% and 40% vs. 29%, respectively), even though the overall frequency of adverse events did not differ (except for hand foot-syndrome). The overall incidence of adverse events leading to permanent interruption was higher in patients with bilirubin >3 mg/dl compared to those with bilirubin <3 mg/dl.
      Other real-practice studies reported similar results, although in smaller patient populations, confirming that sorafenib is frequently used in clinical practice even in patients with Child-Pugh B cirrhosis in many countries.
      • Granito A.
      • Bolondi L.
      Non-transplant therapies for patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B cirrhosis.
      In patients terminating sorafenib, pre-treatment (i.e. pre-sorafenib) Child-Pugh class A was maintained in 59/90 (65.6%) patients and pre-treatment Child-Pugh B was improved to A in 10/35 (28.6%) patients when sorafenib ceased. However, in patients terminating sorafenib it is often difficult or impossible to distinguish whether liver functional worsening is due to a specific drug impact or to a reduction in non-tumoural parenchyma (as a result of tumour progression). To summarise, poor liver functional reserve does not affect the safety of sorafenib (in terms of global risk of adverse events), but overall survival of patients with Child-Pugh B cirrhosis is poor, as expected, and noticeably worse than in patients with Child-Pugh A cirrhosis.
      Limited data is available on lenvatinib, the other approved first-line tyrosine kinase inhibitor (TKI) for advanced HCC in most countries, in patients with a degree of liver dysfunction greater than Child-Pugh class A. In the registration trial, 99% of patients had Child-Pugh A cirrhosis. Specific data in patients with Child-Pugh B cirrhosis were therefore limited to 11 patients included in a phase I study. The safety profile was found to be comparable between Child-Pugh A and B, except for any grade and grade 3 hyperbilirubinemia, which occurred more often in patients with Child-Pugh B cirrhosis (72% and 27% vs. 22% and 11% for Child-Pugh A, respectively).
      • Ikeda M.
      • Okusaka T.
      • Mitsunaga S.
      • Ueno H.
      • Tamai T.
      • Suzuki T.
      • et al.
      Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma.
      Some additional, but still very limited, data come from real-life practice in Japan, though the safety and efficacy of lenvatinib in patients with Child-Pugh B cirrhosis were either not separately reported or, if reported, usually limited to less than 10-20 patients. Nevertheless, one such study on 237 patients showed worse overall and progression-free survival in ALBI grade 2b-3 (106 patients) than in 1-2 a (131 patients), with hazard ratios of 2.34 and 1.52, respectively.
      • Tada T.
      • Kumada T.
      • Hiraoka A.
      • Michitaka K.
      • Atsukawa M.
      • Hirooka M.
      • et al.
      Neutrophil-to-lymphocyte ratio is associated with survival in patients with unresectable hepatocellular carcinoma treated with lenvatinib.
      This study also included 31 patients with Child-Pugh B and 2 with Child-Pugh C cirrhosis, but the results for these groups were not reported separately.
      Poor liver functional reserve appears to somehow decrease TKI tolerability, but it does not impact the general safety of the treatment and is almost never associated with irreversible liver damage. Conversely, treatment tolerability seems similar in patients with poor or good baseline liver functional reserve receiving ICIs. Regardless of the type of systemic treatment (TKI or ICI), poorer baseline liver function is associated with worse overall survival.
      Among second-line systemic therapies, regorafenib, cabozantinib, and ramucirumab registration trials admitted only patients with Child-Pugh class A.
      • 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 α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Patients with a higher degree of liver dysfunction were not included in the trials and large post-marketing studies have not been published in full.
      Only limited data in 59 patients with Child-Pugh B cirrhosis were reported for regorafenib
      • Kim H.D.
      • Bang Y.
      • Lee M.A.
      • Kim J.W.
      • Kim J.H.
      • Chon H.J.
      • et al.
      Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: a multicentre retrospective study.
      showing shorter survival and higher risk of jaundice in ALBI class 3 than 1-2. In addition, some preliminary reports about regorafenib are available from REFINE (NCT03289273), an ongoing real-life observational international multicentre study enrolling patients with HCC for whom a decision to treat with regorafenib was made by the treating physician prior to enrolment, according to the local health authority approved label. Findings from the interim analysis performed after the first 500 enrolled patients have only been presented at a conference, the 2020 meeting of the International Liver Cancer Association.
      • Merle P.
      • Lim H.Y.
      • Finn R.S.
      • Ikeda M.
      • Kudo M.
      • Frenette C.T.
      • et al.
      Sequential treatment with sorafenib followed by regorafenib in patients with unresectable hepatocellular carcinoma (HCC): interim analysis of the observational REFINE study.
      In the REFINE study there is a broader patient population compared with RESORCE, reflecting the less stringent inclusion criteria of the clinical-practice study, with 11% of patients having Child-Pugh class B. Interestingly, overall survival was also calculated according to the Child-Pugh class and ALBI grade at study entry in patients who had previously received sorafenib. The median overall survival was 16.0 months in the Child-Pugh class A group (95% CI 13.1-18.8) vs. 8.0 months in the Child-Pugh B group (95% CI 5.2-not evaluable [NE]). The median overall survival in patients in ALBI grades 1, 2, and 3 was 19.6 (95% CI 14.8-19.6), 10.5 (95% CI 8.7-16.0), and 3.1 (95% CI 1.6-8.7) months, respectively.
      All in all, the historical data on patients with moderately impaired liver function (Child-Pugh B or ALBI 2) who progress on sorafenib before any second-line therapy had become available, would suggest that regorafenib is at least not detrimental in such populations and does not significantly impact liver function.
      Briefly, besides what is reported for sorafenib and partially for regorafenib, there is currently limited data about the efficacy and safety of TKI therapies in categories of patients with more severe liver dysfunction
      • 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 α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      and any conclusion about the impact of such drugs in patients with reduced liver functional reserve cannot be drawn, apart from the expected prognostic impact of worse liver function.
      Immune checkpoint inhibitors (ICIs) have been the most significant innovation in oncology in recent years and were in fact tested in HCC, providing interesting efficacy results in various phase I-III trials, with a recent positive phase III trial reporting the superiority of the combination of atezolizumab and bevacizumab over sorafenib.
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
      Most studies have been restricted to patients with optimal liver functional reserve, leaving the question open about the safety and efficacy of ICIs in patients with poorer liver functional reserve. Worthy of note is that adverse events occurring under ICIs may be less frequent but may last longer (being immune mediated) than those under TKIs; steroid treatment may also be required for ICI-related adverse events. Therefore, the question arises as to whether such longer lasting adverse events may have a greater impact on patients in Child-Pugh class B, who may not have enough reserve to tolerate a problem of longer duration, though the occurrence of severe adverse events may be rarer. Dedicated studies are therefore eagerly awaited.
      Baseline liver functional reserve predicts the risk of toxicity after external radiotherapy and the risk is consistently higher in patients with poor liver function, such as patients with Child-Pugh B class or poorer ALBI score. A worse liver function before external radiotherapy is a predictor of worse outcomes.
      Recently, in a retrospective clinical study evaluating the outcomes and safety of nivolumab in 132 patients with class A and 71 with class B cirrhosis, the objective response rate was lower in patients with Child-Pugh class B than A (2.8% vs. 15.9%; p = 0.010) and class B was an independent negative predictor of objective response. Median overall survival was significantly shorter in patients with Child-Pugh class B (11.3 vs. 42.9 weeks; adjusted hazard ratio, 2.10; p <0.001). Overall survival of patients with Child-Pugh class B, but with a score of 8 or 9 was worse than that of patients with a Child-Pugh score of 7 (7.4 vs. 15.3 weeks; hazard ratio, 1.93; p <0.020). Five (3.8%) patients in the Child-Pugh A group and 1 (1.4%) patient in the Child-Pugh B group had grade 3 or higher toxicities that were probably attributable to nivolumab, leading to drug discontinuation.
      • Choi W.M.
      • Lee D.
      • Shim J.H.
      • Kim K.M.
      • Lim Y.S.
      • Lee H.C.
      • et al.
      Effectiveness and safety of nivolumab in child–pugh b patients with hepatocellular carcinoma: a real-world cohort study.
      A recent cohort study of 49 patients with Child-Pugh B7-8 cirrhosis in the CheckMate-040 study demonstrated similar safety profiles without higher rates of discontinuation compared to patients with Child-Pugh class A from the dose-escalation and -expansion trial (24.5% grade 3 or 4 drug-related adverse events vs. 22.5%, respectively).
      • 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.
      ,
      • Kudo M.
      • Matilla A.
      • Santoro A.
      • Melero I.
      • Gracián A.C.
      • Acosta-Rivera M.
      • et al.
      CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.
      In a retrospective case series of patients with advanced HCC treated with nivolumab, immune-related adverse events were reported to occur in approximately 50% of patients with Child-Pugh B cirrhosis,
      • Kambhampati S.
      • Bauer K.E.
      • Bracci P.M.
      • Keenan B.P.
      • Behr S.C.
      • Gordan J.D.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: safety and clinical outcomes in a retrospective case series.
      a rate similar to that of patients with Child-Pugh A in the CheckMate 040 trial. Among patients with Child-Pugh B cirrhosis, 28% required steroids. In summary, ICIs seem to hold promise for patients with impaired functional reserve, but further data are required to draw any firm conclusions.
      Although never evaluated in randomised controlled clinical trials, cohort studies have shown promising antitumour activity and a good safety profile of metronomic capecitabine therapy in patients with Child-Pugh B cirrhosis, almost invariably with bilirubin <3 mg/dl and without tense ascites. Therefore, this therapy may be considered in this category of patients, but only when other systemic therapies cannot be used because of prescription limits or a high risk of toxicity.
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      Data on the impact of systemic therapies on liver function are more limited. Again, more data are available for sorafenib. Real-world studies have reported that patients with Child-Pugh B cirrhosis generally have a higher frequency of liver function deterioration
      • Granito A.
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      (Table S2). In a small retrospective study assessing lenvatinib as an initial treatment in patients with intermediate-stage HCC with large or multinodular tumours exceeding the up-to-seven criteria, ALBI score was maintained at the end of treatment.
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      A recent real-life Japanese prospective observational study compared 45 patients treated with lenvatinib to 135 patients treated with sorafenib and selected through a propensity score matching analysis. More patients treated with lenvatinib had a Child-Pugh score that was maintained or improved after 4 and 12 weeks compared to those treated with sorafenib (p = 0.048, p = 0.036, respectively).
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      Multivariate analysis revealed that a worsened Child-Pugh score after 4 weeks was an independent unfavourable predictive factor for overall survival.
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      Lastly, an exploratory analysis of the REACH and REACH-2 studies showed that ramucirumab did not negatively affect liver function, as measured by the ALBI score and grade, when compared with placebo.
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      External radiotherapy

      Liver cancer is a radiosensitive tumour, however, the use of radiotherapy for the treatment of liver neoplasms has been limited because of the poor tolerance of the whole liver to radiotherapy and the consequent risk of liver toxicity. The classical toxicity of radiation, called RILD (radiation-induced liver disease), usually appears in the form of a veno-occlusive disease characterised by obliteration of the central vein due to red blood cell entrapment by fibrous tissue, sinusoidal congestion and centrilobular hypoxic necrosis.
      • Lawrence T.S.
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      • Fajardo L.F.
      Hepatic toxicity resulting from cancer treatment.
      Besides the classical RILD, a non-classical RILD has been described. It consists of a worsening of liver laboratory parameters (increase in alkaline phosphatase and transaminases) and/or an increase in Child-Pugh score by 2 points compared to baseline, with no evidence of tumour progression.
      • Guha C.
      • Kavanagh B.D.
      Hepatic radiation toxicity: avoidance and amelioration.
      ,
      • Dawson L.A.
      • Ten Haken R.K.
      Partial volume tolerance of the liver to radiation.
      The risk of RILD is directly related to the amount of radiation received by the liver parenchyma; it may be reduced by fractioning the delivery of the total radiation load and depends on the degree of liver dysfunction.
      Baseline liver functional reserve is a critical predictor of the occurrence of RILD and the risk is consistently higher in patients with poor liver function, such as patients with Child-Pugh class B cirrhosis.
      • Liang S.X.
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      • et al.
      Hypofractionated three-dimensional conformal radiation therapy for primary liver carcinoma.
      ALBI score showed a performance similar to the Child-Pugh score in predicting RILD after stereotactic body radiation therapy and patients with an ALBI grade of 2 have a higher risk of radiation toxicity compared to patients with ALBI grade 1.
      • Murray L.J.
      • Sykes J.
      • Brierley J.
      • Kim J.J.
      • Wong R.K.S.
      • Ringash J.
      • et al.
      Baseline albumin-bilirubin (ALBI) score in western patients with hepatocellular carcinoma treated with stereotactic body radiation therapy (SBRT).
      ,
      • Su T.S.
      • Yang H.M.
      • Zhou Y.
      • Huang Y.
      • Liang P.
      • Cheng T.
      • et al.
      Albumin - bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy.
      From the perspective of liver function, ideal candidates for external radiation therapy with new optimised methodologies (including nuclear medicine techniques for the calculation of activity to be delivered) should have a preserved liver function based on Child-Pugh or ALBI score and a functional non-tumour volume larger than 700 ml. The main factors that should be considered before treatment with external radiotherapy are reported in Table 4.

      Conclusions

      Based on the literature that we have summarised for each non-surgical treatment and the real-life experience of the authors, we propose a new treatment algorithm, which is presented in Fig. 2, taking liver functional reserve as a starting point. We propose 4 subclasses of liver functional reserve (optimal, suboptimal, intermediate, and poor) that are to be matched with an estimate of tumour bulk in order to support therapeutic decision making.
      Figure thumbnail gr2
      Fig. 2Flowchart of treatment strategy design in non-surgical patients with HCC according to the degree of liver functional reserve and tumour burden.
      Treatment options are displayed with a degree of gray shades according to the strength of evidence for their indications. Lighter shades of gray indicate weaker evidence for benefit.
      In conclusion, patients with compensated cirrhosis and large liver functional reserve can always receive the most radical treatment in terms of potential survival benefit according to their tumour stage, provided that there is no significant extrahepatic disease. Conversely, a more detailed and individualised assessment should be carried out in patients with poorer liver functional reserve. Such assessment must balance the expected antitumor efficacy of any given locoregional therapy with the risk of deterioration in liver function, especially considering the risk of progression to frank Child-Pugh class B or borderline Child-Pugh class A, which may limit the possibility to receive multiple lines of systemic therapy, whose clinical potential is rapidly increasing. Therefore, multispecialty tumour boards aimed at providing the most refined and innovative therapies based on each individual patient's condition are becoming of ever greater importance. The most balanced and potentially most complete treatment strategy should be foreseen and designed from the outset, considering the potential for several lines of therapy and not just the one most readily available.

      Abbreviations

      ALBI, albumin-bilirubin; BCLC, Barcelona Clinic liver cancer; HCC, hepatocellular carcinoma; ICG, indocyanine green; ICI, immune checkpoint inhibitors; INR, international normalised ratio; MELD, model for end-stage liver disease; REILD, radioembolisation-induced liver disease; RILD, radiation-induced liver disease; TKI, tyrosine kinase inhibitor; Y90, Yttrium 90.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      All authors equally contributed to the analysis of the literature, to manuscript writing and to all round of revisions.

      Conflicts of interest

      DD: lecture and consulting for Novartis and Alnylam. MdT: none. AG: none. FP: Alkermes, Astrazeneca, Bayer, Bracco, BMS, EISAI, GE, Tiziana Life Sciences, Siemens Healthcare, Roche, Samsung.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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