Prognostic Impact of the Systemic Immune-Inflammation Index in Unresectable Hepatocellular Carcinoma Undergoing Second-Line Combination Therapy: A Multicenter Study

Introduction: Patients with advanced hepatocellular carcinoma (HCC) who progress after first-line systemic therapy face a poor prognosis. This study evaluated the prognostic value of the baseline systemic immune-inflammation index (SII) in patients with unresectable HCC receiving second-line regorafenib, immune checkpoint inhibitors (ICIs), and transarterial chemoembolization (TACE). Methods: This multicenter, retrospective study included a cohort of 118 patients with unresectable HCC who experienced disease progression on first-line systemic treatment. To avoid the optimism bias and overfitting associated with data-derived binary cut-offs, the baseline SII was log-transformed and rigorously evaluated as a continuous variable. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed using multivariate Cox proportional hazards models adjusted for key clinical confounders. Results: In the multivariate analysis, the continuous log-transformed SII emerged as an independent prognostic factor. Each 1-unit increase in the log-SII was significantly associated with a 33% increased risk of disease progression (Adjusted Hazard Ratio HR = 1.33, 95% CI: 1.06– 1.68, P = 0.015) and a 50% increased risk of overall mortality (Adjusted HR = 1.50, 95% CI: 1.08– 2.09, P = 0.017). Subgroup analyses confirmed the consistency of these prognostic trends regardless of the regorafenib starting dose or the specific type of ICI administered. Notably, while baseline SII levels were not associated with objective response rates (ORR), they were significantly associated with an increased risk of severe treatment-related adverse events, underscoring its role as both a prognostic biomarker and a potential indicator of treatment tolerance. Conclusion: Baseline SII, when evaluated as a continuous variable, is a statistically significant and non-invasive prognostic biomarker for patients with unresectable HCC receiving second-line triple therapy. While its discriminatory ability as a standalone tool is modest, it serves as a useful clinical parameter for risk stratification when integrated with established hepatic and tumor burden indices. Keywords: hepatocellular carcinoma, systemic immune-inflammation index, regorafenib, immune checkpoint inhibitors, TACE, prognosis