Barcelona Clinic Liver Cancer 2022 update: Linking prognosis prediction and evidence‐based treatment recommendation with multidisciplinary clinical decision‐making

Hepatocellular carcinoma (HCC) is one of the most frequent and lethal neoplasia worldwide and the leading cause of death and transplant indication among patients with cirrhosis. In the majority of cases, HCC affects patients with underlying liver disease and cirrhosis, which results in the need for careful assessment of both tumour burden and liver function at the time of prognostic prediction and treatment decision. Prognosis assessment is indeed one of the main issues that physicians must face once HCC is diagnosed. Until a few decades ago, there was not much choice, as most of the patients were diagnosed at an advanced symptomatic stage that usually appeared with liver decompensation, and prognosis was consequently dismal. Few patients were diagnosed at an early stage when potentially curative treatments (surgical resection, ablation, or liver transplantation [LT]) could be offered. In between, we found patients with very heterogeneous profiles according to liver function (Child–Pugh A and B), tumour burden (liver-limited or with vascular invasion and/or extrahepatic dissemination) and the presence/absence of symptoms. The presence of constitutional syndrome and cancer-related symptoms as per ECOG performance status, vascular invasion, and/or extrahepatic spread was identified as independent predictors of survival in a cohort of untreated patients prospectively followed in the setting of two clinical trials.1 This evidence first allowed the distinction between intermediate stage HCC, defined by the absence of any adverse predictor, and advanced stage HCC, when symptoms and/or vascular invasion and/or extrahepatic spread were present. This distinction allowed the development of the first Barcelona Clinic Liver Cancer (BCLC) staging system.2 The BCLC proposal constitutes an evolving approach and it has been regularly updated and refined, incorporating all advancements that emerged since its original publication.3-8 In the last years, HCC management has profoundly changed because of improved diagnostic capacity, the refinement of prognosis assessment, and particularly the evidence-based approval of several effective treatment approaches. All those relevant advancements have been incorporated in the most updated BCLC model (Figure 1).9 Differently from previous editions, which were developed exclusively by BCLC members, this update included non-BCLC experts among authors, with the intent to integrate different knowledge, insights and expertise. No major changes in prognosis assessment were implemented except for the inclusion of alpha-fetoprotein (AFP) values as a relevant prognostic factor regardless of the tumour burden and the recognition of the value of the albumin–bilirubin score10 for refining liver function assessment in patients with compensated chronic liver disease. However, the document highlights that the clinical decision-making and treatment recommendations should not only rely on a simplified figure based on tumour burden, liver function and the presence of symptoms, but the ultimate decision must be taken by the responsible physician and tumour board based on a complex process that requires to integrate all those data with the individual patient’s medical profile. Importantly, two novel concepts were introduced: treatment stage migration (TSM) and untreatable progression.6 The TSM applies when the first-line therapy as per stage is not feasible because of an individual patient’s condition. In those cases, the next most suitable option within the same stage or the treatment for a more advanced-stage tumour should be considered. Untreatable progression is defined when either treatment failure or progression after the selected treatment approach occur, but patients still fit into their initial BCLC stage, thus warranting the consideration of a therapy corresponding to a more advanced stage. In the clinical decision-making, the major update was implemented in the intermediate stage. As well known, the intermediate stage is defined as multifocal HCC (beyond BCLC-A criteria; see Figure 1) with preserved liver function, no cancer-related symptoms, and no vascular invasion or extrahepatic spread. However, the tumour burden may be quite heterogeneous in this stage, and prognosis is also influenced by the degree of liver function impairment (even within Child-Pugh class A) and AFP concentration. The updated 2022 BCLC version stratifies the intermediate stage into three subcategories according to tumour burden and liver function. The first subgroup includes patients with well-defined HCC nodules, who could be candidates for LT if they meet the local extended criteria for LT based on tumour burden and AFP levels. The second subgroup includes patients exceeding the extended criteria for LT, but who have preserved portal flow, adequate liver function and well-defined tumour burden. These are good candidates for transarterial chemoembolization (TACE). Finally, the third subgroup comprises patients with infiltrative, diffuse, extensive HCC liver involvement, but who are still asymptomatic and have preserved liver function. They do not benefit from TACE, and systemic therapy should be considered. The most relevant advances have occurred in systemic therapy. The positive results of the IMBRAVE-150 trial, demonstrating the superiority of Atezolizumab plus Bevacizumab (Atezo-Bev) over sorafenib, the standard of care in the first-line setting during the last decade, have completely changed the treatment landscape of HCC, revolutionizing the treatment approach and significantly expanding the survival of patients with advanced HCC.11 More recently, a single priming dose of tremelimumab added to durvalumab (Treme–Durva) every 4 weeks conferred a statistically significant overall survival (OS) benefit versus sorafenib in first line.12 Furthermore, the combination of sintilimab and IBI-305 (a bevacizumab biosimilar) showed an increase in OS and progression-free survival compared to sorafenib in first line in an interim analysis of a phase 2/3 trial conducted in China including patients with unresectable HBV-associated HCC.13 These positive trials suggest that combinations between different classes of immune checkpoint inhibitors (ICIs) or ICI associated with tyrosine kinase inhibitors (TKIs) will constitute the backbone of systemic treatment in the years to come. As a consequence, the treatment landscape for advanced HCC has, however, gained complexity, becoming a huge clinical challenge. The selection of the most adequate option should be based on the careful analysis of the clinical and biochemical profile of the patients according to the specific inclusion and exclusion criteria for each agent in registration trials. Prospective data in real life are informative and may expand the treatment indication, but will never replace the strength of randomized trials as evidence for survival benefit. In real life, a relevant proportion of patients with advanced HCC may not be appropriate candidates for either Atezo–Bev or Treme–Durva and for them, sorafenib or lenvatinib could still be considered. Finally, when sorafenib was the single effective option in the first-line setting, the transition to second line was based on robust evidence14: regorafenib if patients were tolerant to sorafenib,15 cabozantinib irrespective of tolerance to sorafenib and also as in third line,16 or ramucirumab if AFP level >400 ng/dl irrespective of tolerance to sorafenib.17 However, since Atezo-Bev or Treme–Durva are now the preferred first-line treatment options,11, 12 the current treatment sequence has gained complexity after treatment interruption because of toxicity or disease progression. It is then now mandatory to evaluate if sorafenib and lenvatinib can be considered as reasonable second-line options, or if their effectiveness is modified after previous exposure to ICIs ± TKIs.18 Additionally, based on the results reported in the Legacy trial, the BCLC 2022 model recognizes the potential usefulness of transarterial radioembolization for the treatment of single tumours smaller to 8 cm,19 when other well-established therapies such as resection, ablation or transplantation are not feasible. Also, downstaging has emerged as a reliable tool for selecting patients for LT, since tumour response to locoregional therapy has been suggested as a valuable surrogate for tumour biological activity. The goal of downstaging is to reduce tumour burden, being meeting the Milan criteria the commonest endpoint for effective downstaging. Despite the lack of a homogeneous definition of successful downstaging, a recent prospective study has demonstrated that downstaging could contribute to the expansion of HCC transplantation criteria.20 Finally, the initial recommendations in the BCLC model are based on robust scientific evidence, but the clinical decision-making section highlights the complexity of management at the individual level and the need to personalize decisions according to a multiparametric assessment by multidisciplinary tumour boards, where different specialties involved in the management of HCC are actively implicated. Ezequiel Mauro is recipient of an EASL Andrew Burroughs short-term fellowship award. Alejandro Forner receives grant support from Instituto de Salud Carlos III (PI18/00542).