Comparative Efficacy of Initial Treatment Strategies in Patients with Transarterial Chemoembolisation-Unsuitable Hepatocellular Carcinoma

Introduction: Transarterial chemoembolisation (TACE) is considered the standard-of-care for patients with intermediate-stage hepatocellular carcinoma (HCC), despite several patients exhibit features that may be associated with suboptimal outcome of treatment - also referred to as TACE-unsuitable. In this study, our aim was to provide real-world evidence that patients who are considered TACE-unsuitable may receive greater benefit by systemic therapy than by TACE. Methods: This study analysed 1,150 patients with TACE-unsuitable HCC, defined according to Asia-Pacific Primary Liver Cancer Expert criteria. Patients were initially treated with TACE (n = 842), sorafenib (n = 96), lenvatinib (n = 62), or atezolizumab/bevacizumab (n = 47). Overall survival (OS) was the primary endpoint. Inverse probability of treatment weighting was applied to adjust for baseline differences. Results: Compared to TACE, atezolizumab/bevacizumab reduced mortality risk (hazard ratio [HR]: 0.47, 95% confidence interval [95% CI]: 0.27-0.80; p = 0.008), lenvatinib was neutral (HR: 0.62, 95% CI: 0.35-1.08; p = 0.091), and sorafenib was associated with increased mortality (HR: 1.85, 95% CI: 1.28-2.65; p = 0.001). OS at 24 months was 60.2% for TACE, 31.9% for sorafenib, 68.3% for lenvatinib, and 70.5% for atezolizumab/bevacizumab (p < 0.0001). The disease control rate was 53.2% with TACE, 47.9% with sorafenib, 67.8% with lenvatinib (p = 0.030 versus TACE; p = 0.025 versus sorafenib), and 75.6% with atezolizumab/bevacizumab (p < 0.001 versus TACE; p < 0.001 versus sorafenib). Conclusions: In TACE-unsuitable patients, systemic treatment with atezolizumab/bevacizumab and, to a lesser extent, lenvatinib is associated with improved outcome compared to TACE. These findings support a paradigm shift in the initial management of intermediate-stage HCC, favouring the early use of systemic therapy in appropriately selected patients.