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<h4>Background</h4>Beta-blockers can reduce recurrence, metastasis, and mortality in various cancers. In this study, we investigated the effect of propranolol, a non-selective beta-blocker on overall survival (OS) in unresectable/metastatic hepatocellular carcinoma (HCC) and on recurrence-free survival (RFS) in resectable, curable HCC.<h4>Methods</h4>Data were retrieved from the Taiwan National Health Insurance Research Database between January 2000 and December 2013. Propranolol users (for >1 year) and non-propranolol users were matched using a 1:2 propensity score in both cohorts.<h4>Results</h4>The unresectable/metastatic HCC cohort comprised 1,560 propranolol users and 3,120 non-propranolol users (control group). On multivariate Cox regression analysis of HCC mortality, propranolol significantly reduced the mortality risk by 22% (hazard ratio [HR] = 0.78, 95% confidence interval [CI] 0.72-0.84, P <0.001). On stratified Cox regression analysis, propranolol also reduced the mortality risk in HCC patients with hepatitis B (HR = 0.92, 95% CI 0.85-0.99, P = 0.045), hepatitis C (HR = 0.85, 95% CI = 0.78-0.92, P = 0.001), liver cirrhosis (HR = 0.78, 95% CI = 0.72-0.85, P <0.001), and diabetes mellitus (HR = 0.87, 95% CI = 0.81-0.94, P = 0.008). The resectable, curable HCC cohort comprised 289 propranolol users and 578 non-propranolol users (control group), but there was no significant difference in RFS (P = 0.762) between propranolol and non-propranolol users.<h4>Conclusion</h4>This study revealed that propranolol could improve OS in unresectable/metastatic HCC.