Optimizing the sequencing and timing of transarterial chemoembolization and systemic therapy in advanced hepatocellular carcinoma.

Abstract

539 Background: Transarterial chemoembolization (TACE) and systemic therapy are widely used treatments for advanced hepatocellular carcinoma (HCC). Although clinical studies have shown benefit from combining TACE with systemic therapy, the optimal sequencing and timing remain uncertain. Methods: This real-world retrospective cohort study used the National Cancer Database (2004–2022) to identify advanced HCC (AJCC stage III-IV) patients who received both TACE and systemic therapy. A pre-specified protocol was developed and reviewed before implementation; IRB approval was not required as data were de-identified. Based on treatment sequence, patients were categorized as TACE-first, systemic-first, or simultaneous (TACE and systemic therapy initiated within 3 days). The primary endpoint was overall survival (OS). Missing data were handled by case-wise deletion. Inverse probability of treatment weighting (IPTW) was applied using baseline covariates, and weighted Kaplan-Meier and Cox models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analyses by AJCC stage and inter-treatment spacing were performed. Among patients who received systemic therapy first, three subgroups were defined according to the interval between systemic initiation and TACE (0-3 days, 4-14 days, and 15-90 days), reflecting the immune response window after systemic therapy. Results: A total of 1,403 patients were included (916 [65.3%] TACE-first, 202 [14.4%] systemic-first, 285 [20.3%] simultaneous). In the overall cohort, systemic-first sequencing significantly improved OS compared with both TACE-first (HR=1.21, 95% CI 1.01-1.46) and simultaneous (HR=1.27, 95% CI 1.03-1.58), while TACE-first and simultaneous group showed no significant difference. Subgroup analyses by stage showed that among stage III patients, systemic-first was superior to TACE-first (HR=0.79, 95% CI 0.69-0.91) but not significantly different from simultaneous (HR=0.88, 95% CI 0.70-1.11). Among stage IV patients, systemic-first was associated with significantly longer OS than both TACE-first (HR=0.78, 95% CI 0.68-0.90) and simultaneous treatment (HR=0.69, 95% CI 0.56-0.85). Among systemic-first patients, those receiving TACE within 4–14 days achieved the best outcomes, with significantly longer survival compared with both the 0–3 day group (HR=0.62, 95% CI 0.50–0.77) and the 15–90 day group (HR=0.63, 95% CI 0.46–0.87). Conclusions: This study suggests that for patients with advanced HCC, initiating systemic therapy first followed by TACE represents the most favorable sequencing strategy, with the greatest benefit observed when TACE is administered within 4-14 days. Further validation of these findings in larger or prospective studies is warranted.