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. 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. 3,4 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%). 4 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.

on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.

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ClinicalTrials.gov Identifier: NCT01657695.

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