Esophagogastric Variceal Bleeding in Cirrhotic Patients with Hepatocellular Carcinoma Receiving Systemic Therapy: A Retrospective Cohort Study

Purpose: Systemic therapy has improved outcomes in advanced hepatocellular carcinoma (HCC), but the risk of esophagogastric variceal (EGV) bleeding remains a concern. This study investigated the incidence and risk factors for EGV bleeding and mortality in cirrhotic HCC patients receiving systemic therapy. Patients and Methods: This single-center retrospective study included cirrhotic patients with intermediate to advanced HCC who initially received systemic therapy with tyrosine kinase inhibitors (TKIs) alone or in combination with anti-programmed cell death-1 antibodies (anti-PD-1). HCC was diagnosed based on histology or typical radiological findings and staged according to the Barcelona Clinic Liver Cancer (BCLC) classification system. EGV bleeding was confirmed by oesophagogastroduodenoscopy. The treatment efficacy was evaluated using the modified Response Evaluation Criteria in Solid Tumors. Results: A total of 263 patients were included, predominantly male (85.9%), with a median age of 59 years. BCLC stages B and C accounted for 59.3% and 40.7% of cases, respectively. The 1-year and 2-year cumulative incidence of EGV bleeding were 16.7% and 21.6%, respectively. Portal vein thrombosis (PVT), ascites, and severe varices were independently associated with 1-year EGV bleeding. The 1-year mortality rate was 6.1%. The mortality was independently associated with EGV bleeding, AFP levels > 400 ng/mL, type of portal vein tumor thrombus, and tumor progression. The overall objective response rate (ORR) was 32.0%, with TKIs plus anti-PD-1 achieving higher ORR than TKIs alone (39.5% vs. 27.7%, P=0.017) without increasing the bleeding risk or mortality (all P> 0.05). Among 162 HBV-related HCC patients receiving long-term antiviral therapy, HBV DNA negative conversion (37.5% vs. 29.6%, P=0.739) and HBsAg decline (− 15.1% vs. − 14.3%, P=0.883) were comparable between TKIs plus anti-PD-1 and TKIs alone group. Conclusion: In cirrhotic patients with advanced HCC, PVT, ascites and high-risk EGV were predictors of variceal bleeding, regardless of the tumor response. TKIs plus anti-PD-1 achieved higher ORR than TKIs alone without increasing EGV bleeding risk or mortality, supporting their use in selected patients with careful assessment of EGV bleeding risk. Study design includes 263 HCC patients receiving initial systemic therapy, divided into TIKs (166) and TIKs plus Anti-PD-1 (97). Outcomes are EGV bleeding, 1-year mortality and alterations of HBV DNA and HBsAg. EGV bleeding cumulative incidence is 16 percent at 1 year and 21 percent at 2 years. Independent risk factors are shown with odds ratios and p-values. Additive risk effect on EGV bleeding is detailed with percentages for 0 to 3 factors. Mortality cumulative incidence is 6 percent at 1 year, with independent risk factors and additive risk effect percentages. Tumor response rates are compared between TIKs alone and TIKs plus anti-PD-1, showing superior rates for combination therapy. HBV DNA negative conversion is 29.6 percent for TIKs alone versus 37.5 percent for TIKs plus anti-PD-1. HBsAg median decline is -14.3 percent for TIKs alone versus -15.1 percent for TIKs plus anti-PD-1.Infographic on systemic therapy efficacy and safety in hepatocellular carcinoma.