Intermediate-stage hepatocellular carcinoma (HCC) remains a therapeutic challenge due to its biological heterogeneity and variable treatment goals.^1,2 The emergence of effective systemic therapies has renewed interest in combining locoregional and systemic approaches to improve outcomes.^1,2 At the 13^th APGCS, Professor Chiun Hsu from National Taiwan University and Professor Chan, Lam Stephen, from The Chinese University of Hong Kong debated whether this combination approach represents the future of treatment for intermediate-stage disease.³

Supporting the motion, Prof. Hsu emphasized that contemporary treatment paradigms are expanding beyond mere survival prolongation toward curative intent.³ Positive phase 3 trials of transcatheter arterial chemoembolization (TACE) combined with immunotherapy and targeted therapy have demonstrated consistent benefits in progression-free survival (PFS) and objective response rate (ORR).³ Many trial patients had relatively limited tumor burden, including a substantial proportion within the up-to-7 criteria and some with Barcelona Clinic Liver Cancer staging system (BCLC) stage A disease, suggesting the possibility of shifting treatment goals from disease control toward downstaging and conversion to curative treatment.³

Prof. Hsu also highlighted the potential immunomodulatory effects of liver-directed therapy through induction of immunogenic cell death, while cautioning that embolization-induced hypoxia may potentially contribute to immunosuppression.³ He emphasized the need to identify the optimal liver-directed and systemic therapies that translate tumor response into meaningful downstaging and conversion to resectability, while preserving liver function and enabling curative approaches through multidisciplinary management.³

Speaking in opposition, Prof. Chan said that while specific subgroups may benefit, current evidence is insufficient to establish it as a universal standard.³ A major concern is the toxicity burden associated with combination regimens, with serious adverse events, treatment discontinuation, treatment-related complications, and treatment-related deaths reported in major phase 3 studies.³ He argued that future strategies should prioritize tolerability, quality of life, and applicability across a broader patient population.³

Preservation of liver function is an equally critical consideration.³ Prior combination studies have demonstrated declines in albumin-bilirubin (ALBI) scores post-treatment, indicating that intensified locoregional therapy may compromise liver function and limit eligibility for subsequent therapies.³

Furthermore, Prof. Chan questioned reliance on PFS surrogacy, noting that overall survival (OS) data across several major trials remain immature or insignificant, with limited proof of increased cure rates.³ He cautioned that higher response rates should not automatically be equated with long-term survival gains.³ Furthermore, many patients achieve durable disease control with TACE monotherapy alone, avoiding the added toxicity, financial cost, and burden of upfront systemic treatment.³ Rather than an empirical combination for all, he advocated for a precision medicine model guided by tumor biology and individual risk profiles.³

This debate highlights two complementary viewpoints in intermediate-stage HCC.³ While Prof. Hsu emphasized the promise of combination therapy to achieve deep responses and curative conversions, Prof. Chan underscored the imperative to balance efficacy against toxicity, hepatic reserve, and patient quality of life.³ Together, these perspectives illustrate that the future of intermediate-stage HCC management will likely depend not only on more effective therapeutic combinations but also on improved biological stratification and individualized multidisciplinary care.³