Background: Improvement of survival rates for hepatocellular carcinoma during the last two decades and related factors are still debated. This study aimed to evaluate the risk of death and the role of prognostic factors in patients with hepatocellular carcinoma diagnosed in 1995–2001 and 2004–2006. Methods: We performed univariate and multivariable survival analyses of subjects with a first hepatocellular carcinoma diagnosis in 1995–2001 and in 2004–2006, all residing in Brescia province, Italy. Mediation analysis of treatment role in survival was conducted. Results: During follow-up (median 21.1 months) 913 subjects died (95.5%). The 1-, 3- and 5-year survival rates were higher for cases diagnosed in 2004–2006 (64.4%, 35.9% and 24.3%) than in 1995–2001 (60.8%, 34.5% and 20.7%). T stage, metastasis, cirrhosis, Child-Pugh class, portal vein invasion, serum creatinine level, treatment approach and diabetes were survival predictors in both periods. Patients with diagnosis in 2004–2006 had 36% lower risk of death than those with diagnosis in 1995–2001 using adjusted Cox proportional hazard model. The association between diagnosis period and risk of death was mediated by changes in treatment approach. Conclusion: We observed a decreased risk of death for first hepatocellular carcinoma diagnosis from 2004–2006 to 1995–2001, which was partially attributable to improvements in treatment approach.
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