A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C.Hepatology. 2010 Apr;51(4):1274-83. Knowing the spontaneous outcome of hepatocellular carcinoma (HCC) is important for designing randomized controlled trials (RCTs) of new therapeutic approaches; however, survival of patients in the absence of treatment is highly variable, and prognostic factors influencing outcomes are incompletely defined. The aims of this meta-analysis were to estimate the 1-year and 2-year survival rates of untreated HCC patients enrolled in RCTs of palliative treatments, and to identify prognostic factors. RCTs evaluating therapies for HCC with placebo or no-treatment arms were identified on MEDLINE through April 2009. Data were combined in a random effect model. Primary outcomes were 1-year and 2-year survival. Thirty studies met the inclusion criteria. The pooled estimates of the survival rates were 17.5% at 1 year (95% confidence interval [95%CI], 11%-27%; range, 0%-75%) and 7.3% at 2 years (95%CI, 3.9%-13%; range, 0%-50%). Heterogeneity among studies was highly significant (P < 0.0001) both for 1-year and 2-year survival, and persisted when RCTs were stratified according to all patient and study features. Through meta-regression, impaired performance status, Child-Pugh B-C class, and presence of portal vein thrombosis were all independently associated with shorter survival. Ascites was strongly linked to a worse outcome in intermediate/advanced Barcelona Clinic Liver Cancer stages. Conclusion: This meta-analysis confirms the heterogeneity of behavior of untreated HCC and provides a sound basis for stratifying patients with HCC according to expected survival in future trials of new anti-cancer agents.