Breaking Kuhn's paradigm in advanced hepatocellular carcinoma
Authors: David J. Pinato
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article on Page 1784 The epistemologist Thomas Kuhn first postulated that no advancement in science may happen without a revolutionary change in the overarching framework governing scientific knowledge. In the evolutionary progress that has defined the management of hepatocellular carcinoma (HCC), delineation of the Barcelona Clinic Liver Cancer (BCLC) system in 1999 has certainly represented one such revolutionary step by facilitating an evidence‐based allocation of curative and palliative treatments.1 The advanced stage of HCC (BCLC C) is, however, composed of a fairly heterogeneous patient population characterized by a combination of features including extrahepatic spread (EHS), macrovascular invasion (MVI), a wide range of Child‐Pugh scores (A5‐B9), and Eastern Cooperative Oncology Group performance status (PS 0‐2). At the time of the BCLC algorithm definition in 1999, no intervention had been proven to extend survival in advanced‐stage disease, highlighting this patient subgroup as an ideal target for prospective clinical studies of novel therapies. The approval of sorafenib as the first effective systemic treatment for HCC in 2008 was to be unfortunately followed by a decade of stagnation in drug development, fueled by the incomplete understanding of the molecular and clinical phenotype of a vastly heterogeneous disease.2 The recent article by Giannini et al.,3 which reports on a scrupulous field‐practice analysis of treatment outcomes in a large multicenter cohort of Italian BCLC C patients, proves the concept that not all patients who fulfill advanced‐stage criteria have uniform survival outcomes. By combining simple and readily available clinical variables including PS, MVI, and EHS, the Italian study proposes a clinicopathologic risk stratification of advanced HCC, similar to the algorithms that currently guide the provision of systemic anticancer treatment in other oncological indications, including renal cell carcinoma4 and germ cell tumors.5 The key finding of this study is the uneven prognostic weight demonstrated for each variable structuring the BCLC C stage. The survival probability reported for patients with PS1 (median survival 38.6 months), achieved as a result of the higher propensity of treating physicians to recommend curative or locoregional therapies, is a provocative finding and suggests that a conspicuous proportion of patients, amounting to nearly half of the studied cohort in the ITA.LI.CA. data set, might tolerate more effective treatments than the standard of care, sorafenib. These findings, as well as the predilection for a "treatment‐stage migration" approach within the BCLC algorithm, are perhaps unsurprising, having been acknowledged in observational studies6 and international guidelines.7 Among the factors responsible for this variation in clinical practice, the evolving precision in the delivery of transarterial chemoembolization has made this a safe and deliverable treatment in patients with PS1 and segmental MVI, strengthening the case for the choice of transarterial chemoembolization as a first‐line treatment in selected BCLC C patients in some institutions.8 As the clinical landscape of advanced HCC continues to evolve to include novel therapeutic options such as yttrium‐90 radioembolization, second‐line systemic therapy with regorafenib, and immune checkpoint inhibitors, selection of the most appropriate treatment for each patient demands a more personalized approach (Fig. 1).Figure 1: Risk stratification of advanced HCC based on common clinicopathologic variables highlights the real‐life challenges in proposing a standardized sequencing of treatments across all patient subgroups to optimize survival outcomes. Abbreviations: TACE, transarterial chemoembolization; TARE, transarterial radioembolization.To put recent advancements into perspective, the improved tolerability of yttrium‐90 radioembolization over sorafenib in MVI+/EHS− patients might suggest the preferential positioning of this therapy in patients with liver‐confined disease.9 Conversely, as the probability of survival deteriorates with advancing tumor burden, in patients with EHS alone or in association with MVI molecularly targeted therapies represent the most rational therapeutic option. However, the higher prevalence of liver dysfunction described within the EHS+/MVI+ and PS2 patient subgroups highlights a non‐negligible limitation to the provision of sorafenib/regorafenib treatment sequencing in routine practice, with similar constraints affecting the clinical positioning of novel molecules including lenvatinib and cabozantinib. Moreover, the overlapping toxicity between kinase inhibitors might also limit the proportion of patients who may benefit from sequential therapy, and certainly such an approach should be considered carefully in patients with a more advanced PS. With the advent of programmed cell‐death 1–targeted immune checkpoint inhibitors, for which no effective response predictor exists, clinical identification of the most suitable candidates for treatment is of even greater relevance, to spare patients from potentially life‐threatening immune‐related toxicity in the absence of clinical benefit.10 Despite being limited by its retrospective design and the geographical origin of the study cohort, which only included Italian patients, the study by Giannini et al. maintains the issue of disease heterogeneity at the top of the clinical and research agenda at a time of paradigm shift in the management of advanced HCC. While the BCLC algorithm remains an optimal, evidence‐based framework for the diagnosis and treatment of patients with HCC, improved disease phenotyping of advanced disease might facilitate clinicians in addressing the uncertainties imposed by a rapidly evolving treatment landscape and help to maximize survival outcomes in advanced HCC.