Editorial: Tumour Burden Score and Extrahepatic Progression After TACE —Refining Risk Stratification Beyond the Liver

Transarterial chemoembolization (TACE) remains a cornerstone treatment for intermediate-stage hepatocellular carcinoma (HCC), and disease progression after TACE is predominantly intrahepatic [1, 2]. Nevertheless, extrahepatic progression (EHP), although relatively uncommon at early stages, represents a critical clinical inflection point that precludes further locoregional therapies (LRT) and necessitates transition to systemic treatment. Besides, the management of intermediate-stage HCC is undergoing a paradigm shift. The recently updated 2026 Barcelona Clinic Liver Cancer (BCLC) strategy acknowledges the heterogeneity of intermediate-stage HCC and refines the therapeutic hierarchy to better allocate patients between LRT and systemic therapies [3]. However, within these broad categories, clinicians continue to face substantial ‘grey zones’, particularly when identifying patients for whom TACE is futile or serves merely as a transient bridge toward EHP. Pinto et al. provide an important navigational tool to address this clinical challenge [4] by analysing a multicentre cohort of 890 patients. The authors validate the tumour burden score (TBS), which integrates tumour size and number, as a robust predictor of EHP [5]. Using a TBS cut-off of 3.66, they demonstrate that patients above this threshold experienced a significantly higher risk of EHP (32.6% vs. 18.7%). In addition, patients with high TBS exhibited a poorer radiological response to TACE, lower rates of curative treatment at progression, and significantly shorter overall survival (OS) and progression-free survival compared with their low-TBS counterparts. These findings are consistent with our previous study showing that TBS could be served as a reliably stratifies OS among patients undergoing TACE across different BCLC stages and albumin-bilirubin (ALBI) grades, underscoring its robustness across diverse clinical settings [5]. The concept that tumour burden critically determines outcomes after TACE is well established. Earlier work analysing intermediate-stage HCC demonstrated that patients with high tumour burden derive limited durable benefit from repeated TACE and should be specifically considered when designing clinical trials comparing TACE with emerging systemic therapies [6]. More recently, a clinical trial evaluating lenvatinib plus pembrolizumab combined with TACE showed that the OS benefit of combination therapy was confined to patients with high TBS, whereas no advantage was observed in the low-TBS subgroup [7]. These findings further support the notion that tumour burden is not only prognostic but also predictive of treatment benefit and should guide therapeutic sequencing. Among available tools to quantify tumour burden, the up-to-seven criteria have been widely used to predict outcomes across different HCC treatment modalities [8, 9]. Notably, although both up-to-seven criteria and TBS were associated with EHP in univariate analysis in the current study, only TBS remained independently predictive in multivariate models. This observation suggests that high TBS is not merely a surrogate for overall mortality risk but more specifically reflects metastatic potential. Furthermore, the combination of high TBS and AFP > 1000 ng/mL identified a subgroup with an exceptionally high risk of EHP (3-year EHP rate of 68.7%), providing a clinically pragmatic definition of ‘unsuitability’ for TACE monotherapy. In such patients, early transition to systemic therapy or integration of combination strategies may be more appropriate than repeated locoregional interventions. In summary, Pinto et al. provide robust evidence that TBS is a clinically actionable marker for anticipating EHP after TACE. When interpreted alongside prior studies on trial design, combination therapy and guideline evolution, these data support a paradigm shift from repetitive locoregional treatment toward biologically informed, personalised treatment strategies for intermediate-stage HCC. Chien-Wei Su: conceptualization, investigation, supervision, validation, writing – original draft, writing – review and editing, methodology, software. The author has nothing to report. Chien-Wei Su: Speakers' bureau: Gilead Sciences, Bristol-Myers Squibb and AbbVie. Advisory arrangements: Gilead Sciences. Grants: Gilead Sciences and Eiger. This article is linked to Pinto et al. paper. To view this article, visit https://doi.org/10.1111/apt.70534. The data that support the findings of this study are available from the corresponding author upon reasonable request.