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BCLC strategy for prognosis prediction and treatment recommendation Barcelona Clinic Liver Cancer (BCLC) staging system. The 2022 update

  • Author Footnotes
    ∗ These authors share the last authorship position.
    M. Reig
    Correspondence
    Corresponding author: BCLC group, Liver Unit, ICMDM, CIBERehd, IDIBAPS, Hospital Clínic, c/ Villarroel, 170, Escala 11, 4a planta, 08036 Barcelona. Spain. Tel.: +34 932279803, fax: +34 932275792.
    Footnotes
    ∗ These authors share the last authorship position.
    Affiliations
    BCLC group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain
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  • A. Forner
    Affiliations
    BCLC group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain
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  • J. Rimola
    Affiliations
    BCLC group, Radiology Department, CDI, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain
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  • J. Ferrer-Fábrega
    Affiliations
    BCLC group, Surgery Department, ICMDM, IDIBAPS, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain
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  • M. Burrel
    Affiliations
    BCLC group, Vascular Department, CDI, Hospital Clinic of Barcelona. Barcelona University. University of Barcelona. Barcelona. Spain
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  • A. Garcia-Criado
    Affiliations
    BCLC group, Radiology Department, CDI, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain
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  • R.K. Kelley
    Affiliations
    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. USA
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  • P.R. Galle
    Affiliations
    Department of Internal Medicine, Mainz University Medical Center, Mainz, Germany
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  • V. Mazzaferro
    Affiliations
    Department of Oncology, University of Milan and HPB Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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  • R. Salem
    Affiliations
    Department of Radiology, Section of Interventional Radiology, Northwestern University, Chicago, IL. USA
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  • B. Sangro
    Affiliations
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain

    Liver Unit, Clinica Universidad de Navarra, Pamplona, Spain
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  • A.G. Singal
    Affiliations
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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  • A. Vogel
    Affiliations
    Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
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  • J. Fuster
    Affiliations
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain

    BCLC group, Surgery Department, ICMDM, IDIBAPS, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain
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  • C. Ayuso
    Affiliations
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain

    BCLC group, Radiology Department, CDI, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain
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  • Author Footnotes
    ∗ These authors share the last authorship position.
    J. Bruix
    Correspondence
    Corresponding author: BCLC group, Liver Unit, ICMDM, CIBERehd, IDIBAPS, Hospital Clínic, c/ Villarroel, 170, Escala 11, 4a planta, 08036 Barcelona. Spain. Tel.: +34 932279803, fax: +34 932275792.
    Footnotes
    ∗ These authors share the last authorship position.
    Affiliations
    BCLC group, Liver Unit, ICMDM, IDIBAPS, Hospital Clinic of Barcelona. University of Barcelona. Barcelona. Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Spain
    Search for articles by this author
  • Author Footnotes
    ∗ These authors share the last authorship position.
Published:November 18, 2021DOI:https://doi.org/10.1016/j.jhep.2021.11.018

      Brief summary

      Treatment for hepatocellular carcinoma (HCC) has experienced major advancements since the last update of the official Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy published in 2018. Advancements in the field have emerged in all areas, but in this manuscript, we present those that have primed a change in the strategy and comment why some encouraging data in select interventions are still considered immature and in need of further research to gain their incorporation into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that is needed to take clinical decisions in individual patients so that the recommendation takes into account all the needed parameters to allow a personalised approach.

      Keywords

      • The updated BCLC strategy for prognosis prediction and treatment recommendation has been updated according to advancements in knowledge
      • Stratification of patients into stages has kept its simplicity adding further refinement according to patient characterization
      • Staging is linked to the 1st option to be considered according to scientific evidence
      • Personalized treatment indication is established according to an expert clinical decision-making process where all dimensions of the patients are taken into account.
      • Therapeutic process in BCLC B patients has to be tailored according to tumor burden and effective downstaging may allow liver transplantation.
      • Evaluation and management of patients with liver cancer has to integrate baseline patients’ profile as well as evolutionary events
      • Tumor progression and/or treatment related adverse events may induce to recommend the treatment for a more advanced stage even if BCLC stage has not changed (treatment stage migration)
      Treatment for hepatocellular carcinoma (HCC) has experienced major advancements since the last update of the official Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy published in 2018 [
      • Llovet J.M.
      • Bru C.
      • Bruix J.
      Prognosis of hepatocellular carcinoma: the BCLC staging classification.
      ,
      • Llovet J.M.
      • Burroughs A.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Forner A.
      • Reig M.
      • Rodriguez De Lope C.
      • Bruix J.
      • de Lope C.R.
      • Bruix J.
      Current strategy for staging and treatment: the BCLC update and future prospects.
      ,
      • Forner A.
      • Llovet J.M.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Forner A.
      • Reig M.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ,
      • Bruix J.
      • Reig M.
      • Sherman M.
      Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma.
      ]. Advancements in the field have emerged in all areas, but in this manuscript, we will present those that have induced a change in the strategy and comment why some encouraging data in select interventions are still considered immature and in need of further research to gain their incorporation into an evidence-based model for clinicians and researchers. Scientific evidence should be properly graded according to study design and while observational studies are informative, their limitations for robust causality inference should be acknowledged [
      • Hernán M.A.
      Methods of Public Health Research - Strengthening Causal Inference from Observational Data.
      ]. While prior updates were developed by BCLC members, we have now included expert authors beyond the BCLC group to integrate different expertise insights and knowledge in this updated version.

      Prognosis prediction and patient characterization

      While there is no controversy in the current stratification of patients according to tumour burden and cancer related symptoms [
      • Schag C.C.
      • Heinrich R.L.
      • Ganz P.A.
      Karnofsky performance status revisited: reliability, validity, and guidelines.
      ,
      • Sorensen J.B.
      • Klee M.
      • Palshof T.
      • Hansen H.H.
      Performance status assessment in cancer patients. An inter-observer variability study.
      ] in prognosis prediction, the evaluation of the underlying liver function already induced to abandon the Child-Pugh classification [
      • Pugh R.N.
      • Murray-Lyon I.M.
      • Dawson J.L.
      • Pietroni M.C.
      • Williams R.
      Transection of the oesophagus for bleeding oesophageal varices.
      ] in the last BCLC version; this aspect deserved again an update. Decompensation of liver disease (jaundice, ascites, encephalopathy) reflects non-preserved liver function irrespective of the Child-Pugh or MELD points [
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • Kremers W.
      • Therneau T.M.
      • Kosberg C.L.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ,
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      • et al.
      Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List.
      ], for which several improvements have been proposed [
      • Kim W.R.
      • Mannalithara A.
      • Heimbach J.K.
      • Kamath P.S.
      • Asrani S.K.
      • Biggins S.W.
      • et al.
      MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era.
      ], but compensated liver function could be stratified with additional granularity by using the Albumin-Bilirubin (ALBI) score [
      • Johnson P.J.
      • Berhane S.
      • Kagebayashi C.
      • Satomura S.
      • Teng M.
      • Reeves H.L.
      • et al.
      Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.
      ,
      • 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.
      ,
      • Scheiner B.
      • Pomej K.
      • Kirstein M.
      • Hucke F.
      • Finkelmeier F.
      • Waidmann O.
      • et al.
      Predicting the outcome of patients with hepatocellular carcinoma treated with immunotherapy-the CRAFITY score.
      ], while also adding AFP concentration irrespective of tumour burden [
      • Singal A.G.
      • Hoshida Y.
      • Pinato D.J.
      • Marrero J.
      • Nault J.C.
      • Paradis V.
      • et al.
      International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma.
      ,
      • Cabibbo G.
      • Maida M.
      • Genco C.
      • Parisi P.
      • Peralta M.
      • Antonucci M.
      • et al.
      Natural history of untreatable hepatocellular carcinoma: A retrospective cohort study.
      ]. These parameters are now included in the 2022 BCLC model (Figure 1), but while they may impact prognosis, they may not abolish the treatment benefit if the degree of liver dysfunction does not exceed the established selection criteria for an optimal outcome. Prior variceal bleeding also reflects more advanced liver disease with clinically significant portal hypertension [
      • de Franchis R.
      • VI Faculty Baveno
      Expanding consensus in portal hypertension.
      ,
      • D’Amico G.
      • Morabito A.
      • D’Amico M.
      • Pasta L.
      • Malizia G.
      • Rebora P.
      • et al.
      Clinical states of cirrhosis and competing risks.
      ,
      • Garcia-Tsao G.
      • Friedman S.
      • Iredale J.
      • Pinzani M.
      Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis.
      ], but history thereof does not necessarily warrant its incorporation into prognosis prediction in patients with liver cancer, while it could still be an important aspect in treatment indication. The degree of ascites and response to therapy also impact prognosis: small radiographic ascites or fluid retention that is controlled by a low sodium diet differs from tense ascites regardless of medical treatment (diuretics and/or paracentesis) with or without renal failure [
      • Tonon M.
      • Piano S.
      • Gambino C.G.
      • Romano A.
      • Pilutti C.
      • Incicco S.
      • et al.
      Outcomes and Mortality of Grade 1 Ascites and Recurrent Ascites in Patients With Cirrhosis.
      ,
      • Llach J.
      • Ginès P.
      • Arroyo V.
      • Rimola A.
      • Titó L.
      • Badalamenti S.
      • et al.
      Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.
      ]. Regarding performance status (PS) assessment [
      • Schag C.C.
      • Heinrich R.L.
      • Ganz P.A.
      Karnofsky performance status revisited: reliability, validity, and guidelines.
      ,
      • Sorensen J.B.
      • Klee M.
      • Palshof T.
      • Hansen H.H.
      Performance status assessment in cancer patients. An inter-observer variability study.
      ], it is important to highlight that PS assessment should incorporate tumour-related symptoms but not baseline symptoms already present prior to cancer diagnosis and thus, related to pre-existing comorbidities. This can be difficult to differentiate when PS impairment is related to liver dysfunction, which may or may not be related to tumour burden.
      Figure thumbnail gr1
      Figure 1Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy in 2022. The BCLC system establishes a prognosis in accordance with the five stages that are linked to first-line treatment recommendation. The expected outcome is expressed as median survival of each tumour stage according to the available scientific evidence. The Clinical Decision-Making for an individualised approach according to the available data on September 15, 2021 is defined by teams responsible for integrating all those data with the individual patient’s medical profile. Note that liver function should be evaluated beyond the conventional Child-Pugh staging. AFP, alfa-fetoprotein; ALBI, Albumin-Bilirubin Child-Pugh; MELD, Model of End-stage Liver Disease; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LT, Liver Transplantation; TACE, transarterial chemoembolization; BSC, Best Supportive Care. *Except for those with tumor burden acceptable for Transplant. ˆ Resection may be considered for single peripheral HCC with adequate remnant liver volume. ++ Full availability of the trial testing the combination of tremelimumab and durvalumab, may incorporate these agents in the first line alternatives.
      Clinical research trials include BCLC staging in the definition of the target population, while at the same time they establish inclusion/exclusion criteria to define the patient’s profile. In clinical practice the evaluation of patients to characterise their status also uses the BCLC staging and simultaneously, includes the expert and insightful personalised approach by the treating physician and multidisciplinary tumour board. This will also consider tumour extension and burden, nutritional status, comorbidities and frailty, age, social status and human values and beliefs. There is still no molecular profiling that may predict a different patients outcome or a higher risk of recurrence after successful surgery or ablation [
      • Pinyol R.
      • Montal R.
      • Bassaganyas L.
      • Sia D.
      • Takayama T.
      • Chau G.-Y.
      • et al.
      Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.
      ] nor predict the best treatment option [
      • Singal A.G.
      • Hoshida Y.
      • Pinato D.J.
      • Marrero J.
      • Nault J.C.
      • Paradis V.
      • et al.
      International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma.
      ].
      As known, clinical practice guidelines and algorithms such as BCLC model [
      • Llovet J.M.
      • Bru C.
      • Bruix J.
      Prognosis of hepatocellular carcinoma: the BCLC staging classification.
      ,
      • Llovet J.M.
      • Burroughs A.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Forner A.
      • Reig M.
      • Rodriguez De Lope C.
      • Bruix J.
      • de Lope C.R.
      • Bruix J.
      Current strategy for staging and treatment: the BCLC update and future prospects.
      ,
      • Forner A.
      • Llovet J.M.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Forner A.
      • Reig M.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ,
      • Bruix J.
      • Reig M.
      • Sherman M.
      Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma.
      ], expose the current status of knowledge and the degree of scientific evidence available for each intervention [
      • Vogel A.
      • Cervantes A.
      • Chau I.
      • Daniele B.
      • Llovet J.
      • Meyer T.
      • et al.
      Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • 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.
      ,
      • Heimbach J.K.
      • Kulik L.M.
      • Finn R.S.
      • Sirlin C.B.
      • Abecassis M.M.
      • Roberts L.R.
      • et al.
      AASLD guidelines for the treatment of hepatocellular carcinoma.
      ,
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ,
      • Gordan J.D.
      • Kennedy E.B.
      • Abou-Alfa G.K.
      • Beg M.S.
      • Brower S.T.
      • Gade T.P.
      • et al.
      Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline.
      ], but the ultimate decision is to be taken by the responsible physician and tumour board who needs to assimilate all variables and recommend a given path of care for the patient as an individual [
      • Pocock S.J.
      • Stone G.W.
      The Primary Outcome Is Positive — Is That Good Enough?.
      ]. The multidisciplinary approach is key from the initial diagnosis and tumour staging until the definition of the best initial and sequential treatment definition. Expert radiologists, interventional radiologists, radiation oncologist, pathologists, nurses, clinicians, surgeons in the field of HCC and palliative care specialists and social workers need to work together for this purpose. Health care teams are responsible for performing and/or interpreting imaging techniques and pathology samples, to ultimately integrate all those data with the individual patient’s medical profile. In this regard, the personalised management of patients exceeds the needed assessment of the factors related to HCC and liver function. Thereby, clinical decision-making and treatment recommendation should not be merely based on a simplified figure but is rather a quite elaborated process that requires expert decision making.

       Treatment

      In the following paragraphs we describe the proposed treatment options for each BCLC stage. We also emphasize that while at first sight a given option is the first to be considered, the expert evaluation blending all the clinical and sociocultural information may result in two important concepts: The Treatment Stage Migration (TSM) and the UnTreatable Progression (UTP) [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ,
      • Forner A.
      • Gilabert M.
      • Bruix J.
      • Raoul J.-L.
      Treatment of intermediate-stage hepatocellular carcinoma.
      ,
      • Bruix J.
      • Reig M.
      • Rimola J.
      • Forner A.
      • Burrel M.
      • Vilana R.
      • et al.
      Clinical decision making and research in hepatocellular carcinoma: Pivotal role of imaging techniques.
      ]. TSM is applied when a specific patient profile may induce a shift of the recommendation to the option that would be considered a priority for a more advanced stage. UTP was developed for patients under transarterial chemoembolizaton (TACE) [
      • Forner A.
      • Gilabert M.
      • Bruix J.
      • Raoul J.-L.
      Treatment of intermediate-stage hepatocellular carcinoma.
      ,
      • Bruix J.
      • Reig M.
      • Rimola J.
      • Forner A.
      • Burrel M.
      • Vilana R.
      • et al.
      Clinical decision making and research in hepatocellular carcinoma: Pivotal role of imaging techniques.
      ] but applies to all BCLC stages and treatments applied. It represents failure of the selected treatment strategy [
      • Templeton A.J.
      • Amir E.
      • Tannock I.F.
      Informative censoring — a neglected cause of bias in oncology trials.
      ]. It emerges when patients present treatment failure or progression but still fit into their initial BCLC stage, thus warranting the consideration of a therapy corresponding to a more advanced stage. The 2022 BCLC treatment strategy (Figure 1) incorporates a specific section to describe the proposed Clinical Decision-Making for an individualised approach according to the available data on September 15, 2021. Clinical trials affecting any stage to improve the current benefits are encouraged to induce further advancements.
      It is worth stressing that while at first sight the BCLC figure displays a given option as the initial one to be considered, a specific profile of an individual patient may induce to shift the recommendation to another one considered a priority for a more advanced stage (TSM concept) [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ]. In some cases, treatment may shift from that recommended at first for early stage, to that recommended to advanced stage, or even to no treatment.

       Very early stage (BCLC 0)

      This is defined as a solitary HCC < 2cm without vascular invasion or extrahepatic spread in a patient with preserved liver function and no cancer-related symptoms.
      BCLC-0 management varies according to the potential access to LT and specific profiles as depicted in the clinical decision-making section. The potential of transplant indication because of high recurrence risk is taken into account as already described in the last BCLC model [
      • Forner A.
      • Reig M.
      • Bruix J.
      Hepatocellular carcinoma.
      ]. Therefore, If transplant would be an option and patients fulfil the criteria for surgery, resection would be the first option. Pathology pattern of increased recurrence risk (microscopic vascular invasion, satellites) may induce their consideration for LT because of such risk [
      • Sala M.
      • Fuster J.
      • Llovet J.M.
      • Navasa M.
      • Sole M.
      • Varela M.
      • et al.
      High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation.
      ,
      • Fuks D.
      • Dokmak S.
      • Paradis V.
      • Diouf M.
      • Durand F.
      • Belghiti J.
      Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis.
      ,
      • Ferrer-Fàbrega J.
      • Forner A.
      • Liccioni A.
      • Miquel R.
      • Molina V.
      • Navasa M.
      • et al.
      Prospective validation of ab initio liver transplantation in hepatocellular carcinoma upon detection of risk factors for recurrence after resection.
      ]. However, local regulations for enlistment and priority policies may preclude effective transplant for BCLC-0 until recurrence is apparent. If LT is not feasible, the first treatment approach would be ablation, with resection having given similar survivals between both options [
      • Cho Y.K.
      • Kim J.K.
      • Kim W.T.
      • Chung J.W.
      Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.
      ,
      • Cucchetti A.
      • Piscaglia F.
      • Cescon M.
      • Colecchia A.
      • Ercolani G.
      • Bolondi L.
      • et al.
      Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma.
      ,
      • Izumi N.
      • Hasegawa K.
      • Nishioka Y.
      • Takayama T.
      • Yamanaka N.
      • Kudo M.
      • et al.
      A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation for small hepatocellular carcinoma (SURF trial).
      ,
      • Doyle A.
      • Gorgen A.
      • Muaddi H.
      • Aravinthan A.D.
      • Issachar A.
      • Mironov O.
      • et al.
      Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3 cm in potentially transplantable patients.
      ]. Those patients with such small HCC who present with severe liver dysfunction/decompensation may be considered for LT if they fulfil the enlistment criteria [
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      ,
      • Yao F.Y.
      • Ferrell L.
      • Bass N.M.
      • Watson J.J.
      • Bacchetti P.
      • Venook A.
      • et al.
      Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.
      ,
      • Mazzaferro V.
      • Llovet J.M.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.
      ,
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Herrero J.I.
      • Sangro B.
      • Pardo F.
      • Quiroga J.
      • Inarrairaegui M.
      • Rotellar F.
      • et al.
      Liver transplantation in patients with hepatocellular carcinoma across Milan criteria.
      ]. If not eligible for LT due to non-HCC factors, patients should be classified as BCLC-D stage because of their dismal survival expectation. Indeed, patients may receive priority because of their end-stage liver status, while the presence of very early HCC is not considered as the reason for enlistment and/or for priority allocation.

       Early stage (BCLC A)

      This is defined as solitary HCC irrespective of size or as a multifocal HCC up to 3 nodules (none of them > 3 cm), without macrovascular invasion, extrahepatic spread or cancer related symptoms (PS-0). Liver function has to be preserved and not have reached LT criteria, at which point the patient would be classified as BCLC stage D because of dismal prognosis outside of LT eligibility. As mentioned above, those patients with liver disease deserving LT consideration should be evaluated in the framework of end-stage liver disease. In such setting, HCC diagnosis could become an exclusion criterion for LT if exceeding the enlistment criteria [
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      ,
      • Yao F.Y.
      • Ferrell L.
      • Bass N.M.
      • Watson J.J.
      • Bacchetti P.
      • Venook A.
      • et al.
      Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.
      ,
      • Mazzaferro V.
      • Llovet J.M.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.
      ,
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Herrero J.I.
      • Sangro B.
      • Pardo F.
      • Quiroga J.
      • Inarrairaegui M.
      • Rotellar F.
      • et al.
      Liver transplantation in patients with hepatocellular carcinoma across Milan criteria.
      ]. If LT is contraindicated due to non-HCC factors, there is no effective option to be offered. Thus, the patient should be classified as BCLC D stage.
      Treatment approach for BCLC A patients varies according to tumour number and degree of liver function impairment.

       Solitary HCC

      Treatment selection in these patients requires a multiparametric approach.[
      • Citterio D.
      • Facciorusso A.
      • Sposito C.
      • Rota R.
      • Bhoori S.
      • Mazzaferro V.
      Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma.
      ] Liver function assessment should be stratified according to the degree of portal hypertension as it has been established that the presence clinically significant portal hypertension (CSPH) (defined by a hepatic venous pressure gradient (HVPG) > 10 mmHg) predicts a higher rate of postoperative complications and a lower long-term survival [
      • Llovet J.M.
      • Fuster J.
      • Bruix J.
      Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.
      ,
      • Berzigotti A.
      • Reig M.
      • Abraldes J.G.
      • Bosch J.
      • Bruix J.
      Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis.
      ,
      • Bruix J.
      • Castells A.
      • Bosch J.
      • Feu F.
      • Fuster J.
      • Garcia-Pagan J.C.
      • et al.
      Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.
      ]. It is important to note that the accuracy of HVPG measurement is controversial in patients with NAFLD [
      • Ferrusquía-Acosta J.
      • Bassegoda O.
      • Turco L.
      • Reverter E.
      • Pellone M.
      • Bianchini M.
      • et al.
      Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis.
      ,
      • Baffy G.
      • Bosch J.
      Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it?.
      ].

       Multifocal within Milan criteria (up to 3 HCC nodules, each ≤ 3 cm)

      Multifocal disease still within the Milan criteria (MC) [
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      ] is better served by LT as ablation and resection are hampered by a high risk of HCC recurrence [
      • Pompili M.
      • Saviano A.
      • de Matthaeis N.
      • Cucchetti A.
      • Ardito F.
      • Federico B.
      • et al.
      Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey.
      ,
      • N’Kontchou G.
      • Mahamoudi A.
      • Aout M.
      • Ganne-Carrie N.
      • Grando V.
      • Coderc E.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma: Long-term results and prognostic factors in 235 Western patients with cirrhosis.
      ,
      • 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.
      ]. If LT is not feasible, it is a matter of debate if outcome after surgery or ablation is better than that offered by TACE [
      • Cucchetti A.
      • Djulbegovic B.
      • Tsalatsanis A.
      • Vitale A.
      • Hozo I.
      • Piscaglia F.
      • et al.
      When to perform hepatic resection for intermediate-stage hepatocellular carcinoma.
      ,
      • Forner A.
      • Gilabert M.
      • Bruix J.
      • Raoul J.-L.
      Heterogeneity of intermediate-stage HCC necessitates personalized management including surgery.
      ]. Prospective clinical research is mandatory to define when surgical resection or ablation should be given priority in up to 3 nodules over TACE. This may provide very competitive survival figures in early-stage patients with preserved liver function and health status, as it is usually requested to proceed with resection.

       Intermediate stage (BCLC-B)

      Patients with multifocal HCC (exceeding BCLC-A criteria) with preserved liver function, no cancer related symptoms (PS 0) and no vascular invasion or extrahepatic spread conform the intermediate BCLC B stage. As well known, the magnitude of tumour burden may be quite heterogeneous in this stage, and prognosis is also influenced by AFP concentration [
      • Takayasu K.
      • Arii S.
      • Ikai I.
      • Omata M.
      • Okita K.
      • Ichida T.
      • et al.
      Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.
      ] and the degree of liver function impairment even if still belonging to Child-Pugh class A [
      • 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.
      ]. However, robust cut-offs to be applied are not available. This individualised profile of the patients may also determine a separate treatment decision favouring LT, TACE or systemic therapy [
      • Galle P.R.
      • Tovoli F.
      • Foerster F.
      • Wörns M.A.
      • Cucchetti A.
      • Bolondi L.
      The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy.
      ,
      • Kloeckner R.
      • Galle P.R.
      • Bruix J.
      Local and Regional Therapies for Hepatocellular Carcinoma.
      ]. The 2022 BCLC version stratifies the BCLC-B into 3 groups of patients according to tumour burden and liver function.
      The first subgroup within BCLC B stage includes patients with well-defined HCC nodules. These patients could be candidates for LT if they meet the ‘Extended Liver Transplant criteria’ according to the criteria of the Institution [

      Mehta N, Bhangui P, Yao FY, Mazzaferro V, Toso C, Akamatsu N, et al. Liver Transplantation for Hepatocellular Carcinoma. Working Group Report from the ILTS Transplant Oncology Consensus Conference. Transplantation 2020:1136–42. https://doi.org/10.1097/TP.0000000000003174.

      ]. Expansion of the criteria for LT has been proposed for several years [
      • Mazzaferro V.
      • Regalia E.
      • Doci R.
      • Andreola S.
      • Pulvirenti A.
      • Bozzetti F.
      • et al.
      Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
      ,
      • Yao F.Y.
      • Ferrell L.
      • Bass N.M.
      • Watson J.J.
      • Bacchetti P.
      • Venook A.
      • et al.
      Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.
      ,
      • Mazzaferro V.
      • Llovet J.M.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.
      ,
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Herrero J.I.
      • Sangro B.
      • Pardo F.
      • Quiroga J.
      • Inarrairaegui M.
      • Rotellar F.
      • et al.
      Liver transplantation in patients with hepatocellular carcinoma across Milan criteria.
      ]. A minor increase in tumour size or number may provide competitive survival figures hampered by a slight increase in recurrence that impairs long term survival [
      • Kwong A.
      • Mehta N.
      Expanding the Limits of Liver Transplantation for Hepatocellular Carcinoma: Is There a Limit?.
      ]. The same has been reported if patients are allowed to develop a limited asymptomatic progression beyond MC [
      • Ferrer-Fàbrega J.
      • Sampson-Dávila J.
      • Forner A.
      • Sapena V.
      • Díaz A.
      • Vilana R.
      • et al.
      Limited tumour progression beyond Milan criteria while on the waiting list does not result in unacceptable impairment of survival.
      ]. Survival may be competitive as compared with those patients within MC, but always at a cost of higher recurrence and lower long-term survival. Accordingly, the decision to accept extended criteria is defined by the impact of such expansion in the transplant access for other indications and the minimal outcome to be achieved in each indication [

      Navasa M, Bruix J. Multifaceted perspective of the waiting list for liver transplantation: the value of pharmacokinetic models. Hepatology n.d.;51:12–15. https://doi.org/10.1002/hep.23332.

      ]. Elevated AFP value predicts a higher risk of HCC recurrence and thus, lowered survival. Several groups have established a concentration limit beyond which LT is not considered [
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Toso C.
      • Meeberg G.
      • Hernandez-Alejandro R.
      • Dufour J.-F.
      • Marotta P.
      • Majno P.
      • et al.
      Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.
      ]. A 1000 ng/dL cut-off value is currently applied as exclusion criteria. While downstaging therapy may induce a reduction of AFP, there are no robust data to define the magnitude and /or duration of the reduction [
      • Mehta N.
      • Dodge J.L.
      • Roberts J.P.
      • Hirose R.
      • Yao F.Y.
      Alpha‐fetoprotein Decrease from >1000 to <500 ng/ml in Patients with Hepatocellular Carcinoma Leads to Improved Post‐Transplant Outcomes.
      ].
      The second subgroup is conformed by patients without option for LT but who have preserved portal flow and defined tumour burden suggesting the feasibility of selective access to feeding tumour arteries. They are candidates for TACE. If patients do neither meet the ‘Extended liver transplant criteria’ nor the TACE criteria to secure optimal outcomes [
      • Forner A.
      • Reig M.
      • Bruix J.
      Hepatocellular carcinoma.
      ,
      • 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.
      ,
      • Kloeckner R.
      • Galle P.R.
      • Bruix J.
      Local and Regional Therapies for Hepatocellular Carcinoma.
      ], they should be considered for systemic therapy.
      The third subgroup within BCLC B includes patients with diffuse, infiltrative, extensive HCC liver involvement. They do not benefit from TACE [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ], and systemic therapy should be the recommended option, although there is no strict cut-off when this is the case.

       Advanced stage (BCLC C)

      This stage includes HCC patients presenting with vascular invasion or extrahepatic spread and still relatively fit as reflected by a PS < 2 at staging work-up and a preserved liver function. BCLC C patients should be evaluated for systemic therapy [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. Different effective options for first-, second- and following lines are currently available if patients fulfil the characteristics defined in the registration trials that led to regulatory approval [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ].
      The combination of atezolizumab with bevacizumab (Atezo-Bev) is currently the first line treatment to be considered since it surpasses the survival benefit offered by 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.
      ,
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      ,
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.-F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ], while it has not been evaluated head-to-head versus Lenvatinib [
      • 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.
      ]. To benefit from Atezo-Bev patients must present preserved liver function (compensated Child-Pugh A if there is underlying cirrhosis) and absence of high-risk stigmata for bleeding on upper endoscopy, e.g., properly treated oesophageal varices and no history of variceal bleeding, in order to minimize bleeding risk. Additional requirements that may prevent treatment include vascular disorders and arterial hypertension, as well as severe autoimmune disorders and prior transplantation [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. On October 15, 2021 the HIMALAYA Phase III trial using a single priming dose of tremelimumab added to durvalumab was announced to provide a statistically significant survival benefit versus sorafenib in 1st-line []. Hence, availability of all the study data will sure impact in clinical decision in such setting.
      After disease progression or toxicity leading to treatment interruption, the treatment landscape has gained complexity [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. Prior to 2020 sorafenib was the single effective option in 1st line where evidence-based treatment sequencing can be proposed [
      • 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.
      ,
      • Finn R.S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • Bodoky G.
      • Pracht M.
      • et al.
      Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial.
      ,
      • Zhu A.X.
      • Kang Y.-K.
      • Yen C.-J.
      • Finn R.S.
      • Galle P.R.
      • Llovet J.M.
      • et al.
      Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. Patients transitioning to the 2nd line setting benefit from regorafenib if they are tolerant to sorafenib [
      • 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.
      ], from cabozantinib irrespective of tolerance to sorafenib [
      • 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.
      ], or ramucirumab if AFP level is > 400 ng/dl and irrespective of tolerance to sorafenib [
      • 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.
      ]. Cabozantinib is also effective as 3rd line [
      • 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.
      ]. A Western trial comparing pembrolizumab vs placebo in 2nd line did not met his OS primary end-point [
      • Finn R.S.
      • Ryoo B.Y.
      • Merle P.
      • Kudo M.
      • Bouattour M.
      • Lim H.Y.
      • et al.
      Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial.
      ], but an Asian trial in a similar population has reported significant survival improvement [].

       End-stage (BCLC D)

      Patients with major cancer related symptoms (PS >2) and/or impaired liver function without option of LT due to HCC burden or non-HCC related factors present poor survival at short term and belong to BCLC D stage [
      • Llovet J.M.
      • Bru C.
      • Bruix J.
      Prognosis of hepatocellular carcinoma: the BCLC staging classification.
      ]. Development of HCC in patients with advanced liver disease who would otherwise be considered for LT may mandate their enlistment if tumour burden does not exceed the established criteria. Accordingly, treatment of HCC will not change the survival expectancy due to chronic liver disease and cancer treatment would be of no benefit. In such instance, symptomatic management and coordination of palliative care is mandatory.
      According to the BCLC proposal the expected median survival of HCC patients should be more than 5 years, 2.5 years, 2 years and 3 months for BCLC 0/A, B, C and D; respectively.

       Clinical Decision-Making

      The 2022 BCLC strategy incorporates the Expert Clinical Decision-Making component (Figure 1). It exposes the different concepts and parameters that physicians and multidisciplinary tumour boards responsible for the patients should integrate to propose a personalised HCC treatment indication.

       BCLC-0 patients

      Decision in BCLC 0 may be modulated by several factors that preclude their feasibility and justify a different recommendation from that proposed in the patient characterization block of the figure.
      Ablation through radiofrequency (RF) or microwave (MW) is the preferred technique [
      • Shiina S.
      • Teratani T.
      • Obi S.
      • Sato S.
      • Tateishi R.
      • Fujishima T.
      • et al.
      A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma.
      ,
      • Germani G.
      • Pleguezuelo M.
      • Gurusamy K.
      • Meyer T.
      • Isgro G.
      • Burroughs A.K.
      Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis.
      ], while ethanol injection (PEI) is still applied in selected patients when there are technical or safety concerns. If ablation (percutaneous or laparoscopic if needed) is not feasible because of any reason (location, availability etc.),[
      • Nault J.-C.
      • Sutter O.
      • Nahon P.
      • Ganne-Carrié N.
      • Séror O.
      Percutaneous treatment of hepatocellular carcinoma: State of the art and innovations.
      ] the patient may be considered for surgical resection with the feasibility and safety assessment detailed in the BCLC A section. When this option is not feasible, TACE is the preferred option.[
      • Burrel M.
      • Reig M.
      • Forner A.
      • Barrufet M.
      • Lope C.R.D.
      • Tremosini S.
      • et al.
      Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design.
      ] Transarterial radioembolization (TARE) is equally effective [
      • Salem R.
      • Johnson G.E.
      • Kim E.
      • Riaz A.
      • Bishay V.
      • Boucher E.
      • et al.
      Yttrium‐90 Radioembolization for the Treatment of Solitary, Unresectable Hepatocellular Carcinoma: The LEGACY Study.
      ]. Stereotactic body radiation bears antitumoral activity but further prospective studies are needed to define it role [
      • Chen C.P.
      Role of External Beam Radiotherapy in Hepatocellular Carcinoma.
      ,
      • Shanker M.D.
      • Moodaley P.
      • Soon W.
      • Liu H.Y.
      • Lee Y.Y.
      • Pryor D.I.
      Stereotactic ablative radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of local control, survival and toxicity outcomes.
      ]. However, while safety and efficacy data are well established for RF and MW, TARE could be considered in patients with single nodules < 8 cm. This new BCLC recommendation is based on the results of the Legacy study [
      • Salem R.
      • Johnson G.E.
      • Kim E.
      • Riaz A.
      • Bishay V.
      • Boucher E.
      • et al.
      Yttrium‐90 Radioembolization for the Treatment of Solitary, Unresectable Hepatocellular Carcinoma: The LEGACY Study.
      ], which included patients with singles nodules less than 8 cm, Child-Pugh A and ECOG-PS 0/1. It is important to emphasize that the median tumour size of the patients included in that study was 2.6 cm (range 0.9-8.1). If the patient is not a candidate for locoregional treatment, the option of systemic treatment should be considered, but always aligned with the inclusion and exclusion criteria for the available agents with proven survival benefit.

       BCLC-A patients

      Resection and ablation by radiofrequency offer the same survival expectancy in HCC < 2 cm [
      • Cho Y.K.
      • Kim J.K.
      • Kim W.T.
      • Chung J.W.
      Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.
      ,
      • Cucchetti A.
      • Piscaglia F.
      • Cescon M.
      • Colecchia A.
      • Ercolani G.
      • Bolondi L.
      • et al.
      Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma.
      ]. Ablation beyond this size is less effective and the lower rate of complete responses and higher rate local recurrences gives priority to resection in such cases. MW achieves a more extensive tumour necrosis as compared to RF and is potentially the best option for those patients with HCC < 4 cm [
      • Yu J.
      • Yu X.
      • Han Z.
      • Cheng Z.
      • Liu F.
      • Zhai H.
      • et al.
      Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial.
      ,
      • Vietti Violi N.
      • Duran R.
      • Guiu B.
      • Cercueil J.-P.
      • Aubé C.
      • Digklia A.
      • et al.
      Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial.
      ,
      • Han J.
      • Fan Y.C.
      • Wang K.
      Radiofrequency ablation versus microwave ablation for early stage hepatocellular carcinoma: A PRISMA-compliant systematic review and meta-analysis.
      ]. Larger tumours may still benefit from resection as size alone should not be considered as a limiting factor for surgical resection, as long as imaging has not identified vascular invasion and the remnant liver volume permits adequate postoperative liver function [
      • Chan A.W.H.
      • Zhong J.
      • Berhane S.
      • Toyoda H.
      • Cucchetti A.
      • Shi K.
      • et al.
      Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection.
      ,
      • Vitale A.
      • Burra P.
      • Frigo A.C.
      • Trevisani F.
      • Farinati F.
      • Spolverato G.
      • et al.
      Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: a multicentre study.
      ]. Radiation lobectomy by TARE may increase remnant liver volume and could be considered in some patients [
      • Vouche M.
      • Lewandowski R.J.
      • Atassi R.
      • Memon K.
      • Gates V.L.
      • Ryu R.K.
      • et al.
      Radiation lobectomy: Time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection.
      ]. Major hepatectomy carries excessive risk in patients with cirrhosis and thus, specific tumour locations may also prevent resection and induce consideration for LT [
      • Citterio D.
      • Facciorusso A.
      • Sposito C.
      • Rota R.
      • Bhoori S.
      • Mazzaferro V.
      Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma.
      ]. In such instances, size may be a limiting factor for LT according to the expanded criteria that may be in place. Finally, large tumours are frequently associated to cancer related symptoms (ex: pain) and this portends poor outcome after resection.
      Upon enlisting patients for LT and if the expected waiting time exceeds 6 months, it is recommended to consider treatment to prevent tumour progression leading to exclusion from transplantation. Ablation, chemoembolization and TARE are the most widely used option for this purpose.
      Laparoscopic/robotic resection allows adequate margins and has a reduced invasiveness with lower postoperative complications and potential non-significant impact in liver function even if there exists CSPH [
      • Sposito C.
      • Battiston C.
      • Facciorusso A.
      • Mazzola M.
      • Muscarà C.
      • Scotti M.
      • et al.
      Propensity score analysis of outcomes following laparoscopic or open liver resection for hepatocellular carcinoma.
      ,
      • Molina V.
      • Sampson-Dávila J.
      • Ferrer J.
      • Fondevila C.
      • Díaz del Gobbo R.
      • Calatayud D.
      • et al.
      Benefits of laparoscopic liver resection in patients with hepatocellular carcinoma and portal hypertension: a case-matched study.
      ,
      • Witowski J.
      • Rubinkiewicz M.
      • Mizera M.
      • Wysocki M.
      • Gajewska N.
      • Sitkowski M.
      • et al.
      Meta-analysis of short- and long-term outcomes after pure laparoscopic versus open liver surgery in hepatocellular carcinoma patients.
      ,
      • Morise Z.
      • Ciria R.
      • Cherqui D.
      • Chen K.-H.
      • Belli G.
      • Wakabayashi G.
      Can we expand the indications for laparoscopic liver resection? A systematic review and meta-analysis of laparoscopic liver resection for patients with hepatocellular carcinoma and chronic liver disease.
      ,
      • Ciria R.
      • Cherqui D.
      • Geller D.A.
      • Briceno J.
      • Wakabayashi G.
      Comparative Short-term Benefits of Laparoscopic Liver Resection: 9000 Cases and Climbing.
      ,
      • Troisi R.I.
      • Berardi G.
      • Morise Z.
      • Cipriani F.
      • Ariizumi S.
      • Sposito C.
      • et al.
      Laparoscopic and open liver resection for hepatocellular carcinoma with Child–Pugh B cirrhosis: multicentre propensity score-matched study.
      ]. These encouraging results may induce a resection recommendation in patients who would be initially selected for ablation, but in whom the peripheral tumour location may contraindicate such approach because of risk of tract seeding if punctured without a protective rim of non-tumoral liver or risk of neighbouring organ damage [
      • Molina V.
      • Sampson-Dávila J.
      • Ferrer J.
      • Fondevila C.
      • Díaz del Gobbo R.
      • Calatayud D.
      • et al.
      Benefits of laparoscopic liver resection in patients with hepatocellular carcinoma and portal hypertension: a case-matched study.
      ]. While an acceptable increased CSPH value has not been defined, it is worth considering that postoperative mortality increases and one year survival decreases in parallel to portal hypertension even if the surgery does not involve the liver [
      • Reverter E.
      • Cirera I.
      • Albillos A.
      • Debernardi-Venon W.
      • Abraldes J.G.
      • Llop E.
      • et al.
      The prognostic role of hepatic venous pressure gradient in cirrhotic patients undergoing elective extrahepatic surgery.
      ].
      As proposed for BCLC 0 stage, if a patient is not a candidate for any of the mentioned approaches the concept of TSM should be applied and treatment with TACE should be considered, as well as TARE in patients who meet the Legacy inclusion criteria [
      • Salem R.
      • Johnson G.E.
      • Kim E.
      • Riaz A.
      • Bishay V.
      • Boucher E.
      • et al.
      Yttrium‐90 Radioembolization for the Treatment of Solitary, Unresectable Hepatocellular Carcinoma: The LEGACY Study.
      ]. This is a retrospective cohort study in which median tumour size was < 3cm and thus, validation by other groups is eagerly awaited. If TARE is also not feasible, patients should be considered for systemic therapy.
      The 2022 version of BCLC staging system does not recommend resection for multinodular HCC within MC. Cohort studies of resection report encouraging survival results [
      • Fukami Y.
      • Kaneoka Y.
      • Maeda A.
      • Kumada T.
      • Tanaka J.
      • Akita T.
      • et al.
      Liver Resection for Multiple Hepatocellular Carcinomas: A Japanese Nationwide Survey.
      ], but prospective data are needed to establish the effectiveness of such approach as compared to locoregional approaches. Thus, TACE is the preferred option if the first treatment option is not feasible. However, large tumours exceeding 8-10 cm are reported to be associated to worse outcome after TACE [
      • Galle P.R.
      • Tovoli F.
      • Foerster F.
      • Wörns M.A.
      • Cucchetti A.
      • Bolondi L.
      The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy.
      ,
      • Raoul J.-L.
      • Forner A.
      • Bolondi L.
      • Cheung T.T.
      • Kloeckner R.
      • de Baere T.
      Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence.
      ], this potentially being related to the potential impairment of portal venous flow due to invasion or compression, rather than to the impact of major tumour necrosis. Furthermore, large tumours are rarely free of symptoms. If these are present the patients should be classified as BCLC C. Indeed, survival of symptomatic patients (PS 1) after TACE is significantly lower than that of patients without them [
      • 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.
      ].

       BCLC-B patients

      For patients to be a candidate for TACE, liver function has to be well preserved. Increased bilirubin beyond 2 mg or slight fluid retention requiring diuretic treatment are associated with increased risk of adverse events and suboptimal survival after TACE [
      • Galle P.R.
      • Tovoli F.
      • Foerster F.
      • Wörns M.A.
      • Cucchetti A.
      • Bolondi L.
      The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy.
      ]. It is not possible to define strict evidence-based criteria to recommend TSM favouring systemic treatment and hence, expert assessment is key to secure optimal care. Currently on-going trials in BCLC B stage comparing TACE vs systemic therapy have detailed inclusion and exclusion criteria and may produce highly useful information that will guide clinical practice.
      TACE might be performed using chemotherapy emulsified in lipiodol followed by gelfoam or any other material injection (conventional TACE) or using drug eluting microspheres (DEB-TACE) [
      • Raoul J.-L.
      • Forner A.
      • Bolondi L.
      • Cheung T.T.
      • Kloeckner R.
      • de Baere T.
      Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence.
      ]. The first is associated to a peak of chemotherapy in the systemic circulation that may increase toxicity and to a higher post-procedural pain, while DEB-TACE has a favourable pharmacokinetic profile.[
      • Varela M.
      • Real M.I.
      • Burrel M.
      • Forner A.
      • Sala M.
      • Brunet M.
      • et al.
      Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics.
      ] Response rate and survival are not different between the two techniques [
      • 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.
      ,
      • 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.
      ]. Thus, each team has to define its preference. Available clinical trials comparing bland embolization to TACE are not informative as the population included does not match the profile of patients who would be recommended to receive TACE treatment [
      • Meyer T.
      • Kirkwood A.
      • Roughton M.
      • Beare S.
      • Tsochatzis E.
      • Yu D.
      • et al.
      A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma.
      ,
      • Brown K.T.
      • Do R.K.
      • Gonen M.
      • Covey A.M.
      • Getrajdman G.I.
      • Sofocleous C.T.
      • et al.
      Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone.
      ]. Metanalytic assessment is hampered by an excessive heterogeneity of the trials available for such evaluation [
      • Facciorusso A.
      • Bellanti F.
      • Villani R.
      • Salvatore V.
      • Muscatiello N.
      • Piscaglia F.
      • et al.
      Transarterial chemoembolization vs bland embolization in hepatocellular carcinoma: A meta-analysis of randomized trials.
      ].
      Systemic treatment is the recommended option for those BCLC-B patients who are not candidates for TACE for any reason [
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
      ,
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      ,
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.-F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.-H.
      • Ikeda K.
      • Piscaglia F.
      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      ,
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.-H.
      • Bodoky G.
      • et al.
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.-L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.-Y.
      • et al.
      Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
      ,
      • Zhu A.X.
      • Kang Y.-K.
      • Yen C.-J.
      • Finn R.S.
      • Galle P.R.
      • Llovet J.M.
      • et al.
      Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. If not candidates for systemic treatment, the option of clinical trials should be considered.
      Although the MC are still largely applied to select HCC patients for LT, an increasing number of studies have shown that acceptable post-LT may be obtained in a selected group of patients at BCLC B stage beyond MC. Several selection criteria that sought to expand the MC have been proposed and revised elsewhere [

      Mehta N, Bhangui P, Yao FY, Mazzaferro V, Toso C, Akamatsu N, et al. Liver Transplantation for Hepatocellular Carcinoma. Working Group Report from the ILTS Transplant Oncology Consensus Conference. Transplantation 2020:1136–42. https://doi.org/10.1097/TP.0000000000003174.

      ]. Consensus on expanded criteria for LT in HCC has not been reached. However, composite criteria that consider surrogates of tumour biology (AFP being the most frequently explored) and response to neoadjuvant treatments, are likely to replace conventional morphological criteria for defining transplant feasibility. Several AFP cut-offs have been used for exclusion from LT [
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Toso C.
      • Meeberg G.
      • Hernandez-Alejandro R.
      • Dufour J.-F.
      • Marotta P.
      • Majno P.
      • et al.
      Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.
      ,
      • Hameed B.
      • Mehta N.
      • Sapisochin G.
      • Roberts J.P.
      • Yao F.Y.
      Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.
      ], with value beyond 1000 ng/mL widely accepted as a contraindication for LT [
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria.
      ,
      • Mazzaferro V.
      • Sposito C.
      • Zhou J.
      • Pinna A.D.
      • De Carlis L.
      • Fan J.
      • et al.
      Metroticket 2.0 Model for Analysis of Competing Risks of Death Following Liver Transplantation for Hepatocellular Carcinoma.
      ,
      • Hameed B.
      • Mehta N.
      • Sapisochin G.
      • Roberts J.P.
      • Yao F.Y.
      Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.
      ]. Patients with an AFP >1000 ng/mL who experienced biochemical response (at least a decrease to less than 500 ng/mL) to locoregional therapies (LRT) have a post-LT outcome comparable to the reported within MC [
      • Mehta N.
      • Dodge J.L.
      • Roberts J.P.
      • Hirose R.
      • Yao F.Y.
      Alpha‐fetoprotein Decrease from >1000 to <500 ng/ml in Patients with Hepatocellular Carcinoma Leads to Improved Post‐Transplant Outcomes.
      ]. Downstaging has emerged as a reliable tool for selecting patients for LT. The goal of downstaging is to reduce tumour burden in order for residual viable tumours to fall within acceptable LT criteria, with MC being the commonest endpoint of downstaging [
      • Mazzaferro V.
      • Citterio D.
      • Bhoori S.
      • Bongini M.
      • Miceli R.
      • De Carlis L.
      • et al.
      Liver transplantation in hepatocellular carcinoma after tumour downstaging: a randomised, controlled, phase 2/3 trial.
      ,
      • Yao F.Y.
      • Mehta N.
      • Flemming J.
      • Dodge J.
      • Hameed B.
      • Fix O.
      • et al.
      Downstaging of hepatocellular cancer before liver transplant: Long-term outcome compared to tumors within Milan criteria.
      ]. The upper limit of where a downstaging approach is considered varies across LT regions. This also affects the specific imaging criteria used to define baseline and post-treatment staging and evaluation of response. There is need to develop further studies to validate such approach and establish how to best apply a downstaging protocol. It is important to note that the need to careful establish the patient profile that defines a good transplant candidate is due to the shortage of donors. It implies a demand to use the available donors to provide the best outcome for the community and not solely focus on individual benefit. Live donation may avoid the donor shortage and the decision to use the same criteria as for cadaveric donors or to accept a moderate expansion or a down-staging success is still controversial [

      Mehta N, Bhangui P, Yao FY, Mazzaferro V, Toso C, Akamatsu N, et al. Liver Transplantation for Hepatocellular Carcinoma. Working Group Report from the ILTS Transplant Oncology Consensus Conference. Transplantation 2020:1136–42. https://doi.org/10.1097/TP.0000000000003174.

      ]. Again, survival may be competitive but the balance between the donor risk and the patient benefit is not homogeneously perceived in different cultural settings.

       BCLC-C patients.

      Atezo-Bev provides survival benefit over sorafenib with some patients exhibiting prolonged complete responses. Real-life data will inform about the proportion of patients excluded from the IMBRAVE 150 clinical trial due to comorbidities or CSPH with risk of bleeding. The combination of tremelimumab and durvalumab has been announced superior to sorafenib and hence, this adds another option for 1st line []. A significant proportion of patients with advanced HCC may not be appropriate candidates for both options and still be considered for TKI (sorafenib or lenvatinib) which have lower risk of significant bleeding [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. In this regard, selection of the most adequate option relies in the careful analysis of the clinical and biochemical profile of the patients so that they fit into the target population enrolled in the trials where safety and efficacy was demonstrated. Prospective studies of data in real life may broaden the treatment indication, but in its absence, the recommendation is to retain the clinical and biochemical profile defined in registration trials [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. Furthermore, real world data may be informative but will never replace the strength of randomised trials to prove survival benefit [
      • Bruix J.
      End-points in clinical trials for liver cancer and their value in evidence based clinical decision making: an unresolved Gordian knot.
      ]. Safety in specific populations may be established but survival benefit in the absence of randomized trials will remain as a suggestion.
      Even though Atezo-Bev is the preferred first-line treatment [
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.-Y.
      • et al.
      Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
      ], and lenvatinib is as effective as sorafenib [
      • 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.
      ], there is a major need to assess if the available second line alternatives retain their effectiveness in patients initially receiving any of these two options. Further, it needs to be evaluated if sorafenib and lenvatinib should be considered as “de facto” 2nd line options or if their effectiveness could be modified after Atezo-Bev [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ,
      • Bruix J.
      End-points in clinical trials for liver cancer and their value in evidence based clinical decision making: an unresolved Gordian knot.
      ]. No robust information is available, thus preventing evidence-based recommendation. Several trials that may clarify some of the current unknowns are currently ongoing and, they may or may not increase the 1st line alternatives and/or change the sequential treatment schedule currently in place [
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma. An EASL position paper.
      ]. In that sense, as the efficacy of new strategies increases in terms of response and reduction of tumour burden, the registered downstaging may allow some patients to benefit from potentially curative options that were initially discarded because of excessive tumour load [
      • Ho W.J.
      • Zhu Q.
      • Durham J.
      • Popovic A.
      • Xavier S.
      • Leatherman J.
      • et al.
      Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity.
      ].
      TARE has also been suggested to be as effective as sorafenib in patients with liver-only involvement [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. However, prospective phase 3 trials comparing it with sorafenib or combining it with sorafenib vs sorafenib alone have failed to demonstrate its superiority and they were not designed to proof non-inferiority [
      • 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.
      ,
      • 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.
      ,
      • Ricke J.
      • Klümpen H.J.
      • Amthauer H.
      • Bargellini I.
      • Bartenstein P.
      • de Toni E.N.
      • et al.
      Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.
      ]. Thereby, no evidence-based recommendation may be made until positive trials are available.

       Evolutionary events and Clinical-Decision making process

       BCLC staging upon progression after initial diagnosis

      It is conventional in Oncology to consider tumour progression as a dismal event that is taken as a reflection of treatment failure and need to transition to another line of therapy [
      • Bruix J.
      End-points in clinical trials for liver cancer and their value in evidence based clinical decision making: an unresolved Gordian knot.
      ]. However, it is well established that patients treated with surgical resection, ablation or TACE may present progression as new intrahepatic sites after successful treating the first tumour nodule. In some instances, treatment may be repeated, and the tumour be again under control with potential complete response [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ]. Indeed, progression may have different patterns with sharply different meaning in terms of prognosis and potential treatment [
      • Reig M.
      • Rimola J.
      • Torres F.
      • Darnell A.
      • Lope C.R.-
      • Forner A.
      • et al.
      Post-progression survival of patients with advanced hepatocellular carcinoma. Rationale for second line trial design.
      ]. This concept was raised years ago for patients treated by TACE [
      • Bruix J.
      • Reig M.
      • Rimola J.
      • Forner A.
      • Burrel M.
      • Vilana R.
      • et al.
      Clinical decision making and research in hepatocellular carcinoma: Pivotal role of imaging techniques.
      ]. Treatment may be successful, but new tumour sites may appear during follow-up. These may be amenable to new TACE if just intrahepatic and the patient profile has not changed in terms of liver function and physical status [
      • Forner A.
      • Gilabert M.
      • Bruix J.
      • Raoul J.-L.
      Treatment of intermediate-stage hepatocellular carcinoma.
      ]. Contrarily, if progression is due to portal vein invasion or extrahepatic spread or cancer related symptoms or liver function is significantly impaired, new TACE sessions are not recommended. In such instance, the patient is registered as presenting untreatable progression and systemic therapy may be considered [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ,
      • Bruix J.
      • Reig M.
      • Rimola J.
      • Forner A.
      • Burrel M.
      • Vilana R.
      • et al.
      Clinical decision making and research in hepatocellular carcinoma: Pivotal role of imaging techniques.
      ]. This specific progression scenario implies a different prognosis and a different treatment recommendation and hence, offers more clinical insight than the commonly used “progression” term. The heterogeneity of tumor progressions and individual patient profiles at progression mandates that the best treatment option requires multidisciplinary team discussion.
      The same need to stratify the pattern of progression has emerged in patients undergoing systemic therapy. Prospective studies have demonstrated that prognosis after progression due to increased growth of known tumour sites or new intrahepatic sites is significantly better than progression due to new extrahepatic involvement or vascular invasion [
      • Reig M.
      • Rimola J.
      • Torres F.
      • Darnell A.
      • Lope C.R.-
      • Forner A.
      • et al.
      Post-progression survival of patients with advanced hepatocellular carcinoma. Rationale for second line trial design.
      ]. This primed the proposal of a BCLC prognostic model upon progression that is depicted in Figure 2 [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ]. As shown, patients may start systemic therapy either in BCLC stage B or C. Those initially at stage B may progress but still stay within the B definitions being classified a BCLCp-B. Those initially at BCLC stage C may show growth of existing lesions or new intrahepatic sites and be classified as BCLCp-C1 or develop new vascular invasion or extrahepatic spread and then be registered as BCLCp-C2 [
      • Reig M.
      • Darnell A.
      • Forner A.
      • Rimola J.
      • Ayuso C.
      • Bruix J.
      Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST.
      ].
      Figure thumbnail gr2
      Figure 2BCLC up on progression. BCLC stratification upon radiology progression. This "BCLC upon progression" (BCLCp) proposal classifies as BCLCp-B those patients who present radiologic progression due to growth of existing nodules 20% or new intrahepatic sites but are still within BCLC-B because of the absence of vascular invasion or extrahepatic spread or cancer-related symptoms (PS 0). Those patients who present radiologic progression and evolve to. BCLC-C or progress within BCLC-C are divided at the time of progression into: BCLCp-C1: those patients who present radiologic progression due to growth of existing nodules 20% or new intrahepatic sites, and BCLCp C2: those patients who present progression due to new extrahepatic lesion and/or vascular invasion.
      The prognostic stratification offered by the classification of patients according to their pattern of progression has been repeatedly validated [
      • Iavarone M.
      • Cabibbo G.
      • Biolato M.
      • Della Corte C.
      • Maida M.
      • Barbara M.
      • et al.
      Predictors of survival of patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib.
      ,
      • Reig M.
      • Galle P.R.
      • Kudo M.
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      ]. While pattern of progression is not a predictor of treatment benefit, it has become a relevant parameter to inform patients and to design and analyse clinical trials where a sound survival assumption of the patients recruited is key to establish the potential impact of new agents in life expectancy [
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      ].
      In summary, we have here updated the BCLC prognostic and treatment strategy. It has incorporated the several novelties in the field of clinical management of HCC and clearly delineated the three steps for patients diagnosed with this cancer. Initial staging serves to stratify patients according to their evolutionary status and is linked to the first treatment option to be recommended. This should be based on the amalgamation of all different patient characteristics that are key to propose the option that is expected to provide the best survival. While the initial recommendations are based on robust scientific evidence the “Clinical Decision Making” displays the complexity at the individual level and the need to personalize decisions at the tumor board level incorporating treatment stage migration and the untreatable progression concepts. However, no algorithm should be expected to be able to provide guidance for each patient. A multiparametric evaluation should be in place for every patient and this should be integrated in Multidisciplinary Tumor Boards where all partners involved in care are actively incorporated. For an effective output of such boards, it is key to have a clearly established initial approach to patients from where to reach individual decisions. The updated BCLC model and its regular update serves this purpose.

      Conflict of interest

      MR: reports consultancy from Bayer, BMS, Roche, Ipsen, Astra Zeneca, Boston Science and Lilly; lecture fees from Bayer, BMS, Gilead, Lilly and ROCHE and travel support from Bayer, BMS, Lilly and Astra Zeneca. Received research funding (to institution) from Bayer and Ipsen.
      AF: reports lecture fees from Bayer, Boston Science, Gilead, and MSD, consultancy fees from Bayer, Astra Zeneca, Roche, SIRTEX, AB Exact Science and Guerbert.
      JR: reports lectures and travel grants from Bayer and Roche
      JFF: reports lecture fees from Bayer
      MB: reports lectures and/or travel support from Boston Science, Terumo, Guerbet and Bayer
      AGC: reports lectures fee from Boston Science, Terumo
      KRK: reports consultancy fees (to self) from Exact Sciences, Genentech/Roche, Gilead. Received travel support from Ipsen. Received research funding (to institution) from Agios, Astra Zeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, Taiho.
      PRG: consultancy fees and/or travel support from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen, Eisai
      VM: Nothing to disclose
      RS: reports consultancy fees from Boston Scientific, Cook, Bard, Genentech, Astrazeneca, Eisai, Sirtex, Siemens, research Support from Boston Scientific
      BS: reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; speaker fees from Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; research grants (to Institution) from BMS and Sirtex Medical.
      AS: has served on advisory boards or consulted for Genentech, Bayer, Eisai, AstraZeneca, BMS, and Exelixis.
      AV: Speaker, consultancy and advisory role: Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Incyte, Ipsen, PierreFabre, MSD, Sirtex, BTG, Servier, Terumo, GSK
      JFu: Nothing to disclose
      CA: reports lectures fee from Bayer
      JB: has consulted for Arqule, Bayer-Shering Pharma, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, MSD, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano, Sanofi; and received research/educational grants from Bayer, and lecture fees from Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen

      Financial support statement

      MR: Dr. Reig’s research is partially supported by Instituto de Salud Carlos III (PI15/00145 and PI18/0358) and from the Spanish Health Ministry (National Strategic Plan against Hepatitis C).
      AF: Dr. Forner’s research is partially supported by Instituto de Salud Carlos III (PI13/01229 and PI18/00542).
      JR: Dr. Rimola’s research is partially supported by grant from European Association for the Study of the Liver (EASL).
      BS: Dr. Sangro’s research is partially supported by ISCIII/EU TRANSCAN-2 (AC16/00065), and Instituto de Salud Carlos III (PI19/00742).
      AS: Dr. Singal’s research is supported by National Institute of Health R01 R01 MD012565. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
      JB: Dr. Bruix’s research is partially supported by Instituto de Salud Carlos III (PI18/00768), the Spanish Health Ministry (National Strategic Plan against Hepatitis C) and AECC (PI044031).
      CIBERehd: is funded by the Instituto de Salud Carlos III.
      Some of the authors of this article are members of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER).

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