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. (HEPATOLOGY 2010;51:1274-1283.)
T he extensive application of surveillance programs for early detection of small (Ͻ5 cm) hepatocellular carcinoma (HCC) has increased the number of tumors detected within the Milan criteria 1 at Barcelona Clinic Liver Cancer (BCLC) stages 0 or A (very early or early), 2 and potentially responsive to curative treatments, such as liver transplantation and percutaneous or surgical ablation. Nonetheless, most patients with HCC (approximately 70%) are diagnosed at BCLC B (intermediate) and C (advanced) stages (approximately 50%) or BCLC D (end stage, approximately 20%). A previous systematic review 5 showed that the survival rates of untreated patients or of those who received placebo in randomized controlled trials (RCTs) of unresectable HCC vary among the studies, ranging from 10% to 72% at 1 year and from 8% to 50% at 2 years.
In the setting of unresectable HCC, an accurate estimate of survival among untreated patients is essential for (1) evaluating the natural history and assessing the validity of biological or radiological surrogate markers, (2) controlling for confounding factors in observational studies, (3) calculating the sample size and stratifying subjects in RCTs, and (4) assessing treatment effect size to formulate therapeutic strategies. Knowledge of the factors influencing the outcome of untreated patients also may be important for interpreting the results of RCTs of different treatments.