Marco Enea

A meta‐analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma

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.)

Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C

BACKGROUND & AIMS Randomised controlled trials (RCTs) show that triple therapy (TT) with peginterferon alfa, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of genotype 1 (G1) chronic hepatitis C (CHC) patients with previous relapse (RR), partial response (PAR), and null-response (NR). We assess the cost-effectiveness of TT compared to no therapy in the treatment of patients previously treated with G1 CHC. METHODS The available published literature provided the data source. The target population was made up of previously treated Caucasian patients with G1 CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro at 2012 value), life years gained (LYG), quality adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER).The robustness of the results was evaluated by one-way deterministic and multivariable probabilistic sensitivity analyses. RESULTS In RR patients, ICER per LYG compared to no therapy was €9555 for BOC-LEAD-IN-RR and €7910 for TVR-LEAD-IN-RR, being BOC dominated by TVR. In PAR patients, ICER for LYG was €11,947 for BOC-LEAD-IN-PAR and €14,931 for TVR-PAR, being TVR cost-effective compared to BOC (ICER for QALY €22,258). In NR patients, ICER for LYG was €26,499 for TVR-LEAD-IN-NR. The models were sensitive to likelihood of sustained virological response and to BOC/TVR prices. CONCLUSIONS 1st generation HCV PI is highly cost-effective compared to no therapy in RR and PAR G1 CHC patients. TVR dominated BOC in RR, and was cost-effective compared to BOC in PAR patients. In NR patients an assessment of the response after a lead-in period should be performed to improve safety and cost-effectiveness.

Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C

Randomized controlled trials (RCTs) show that triple therapy (TT) with peginterferon alpha, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon‐ribavirin dual therapy (DT) in the treatment of previously untreated patients with genotype 1 (G1) chronic hepatitis C (CHC). We assessed the cost‐effectiveness of TT compared to DT in the treatment of untreated patients with G1 CHC. We created a Markov Decision Model to evaluate, in untreated Caucasian patients age 50 years, weight 70 kg, with G1 CHC and Metavir F2 liver fibrosis score, for a time horizon of 20 years, the cost‐effectiveness of the following five competing strategies: 1) boceprevir response‐guided therapy (BOC‐RGT); 2) boceprevir IL28B genotype‐guided strategy (BOC‐IL28B); 3) boceprevir rapid virologic response (RVR)‐guided strategy (BOC‐RVR); 4) telaprevir response‐guided therapy (TVR‐RGT); 5) telaprevir IL28B genotype‐guided strategy (TVR‐IL28B). Outcomes included life‐years gained (LYG), costs (in 2011 euros) and incremental cost‐effectiveness ratio (ICER). In the base‐case analysis BOC‐RVR and TVR‐IL28B strategies were the most effective and cost‐effective of evaluated strategies. LYG was 4.04 with BOC‐RVR and 4.42 with TVR‐IL28B. ICER compared with DT was €8.304 per LYG for BOC‐RVR and €11.455 per LYG for TVR‐IL28B. The model was highly sensitive to IL28B CC genotype, likelihood of RVR and sustained virologic response, and BOC/TVR prices. Conclusion: In untreated G1 CHC patients age 50 years, TT with first‐generation protease inhibitors is cost‐effective compared with DT. Multiple strategies to reduce costs and improve effectiveness include RVR or genotype‐guided treatment. (HEPATOLOGY 2012;56:850–860)

Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems

Background  A major problem in assessing the likelihood of survival of patients with hepatocellular carcinoma (HCC) arises from a lack of models capable of predicting outcome accurately.

Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.

We assessed the cost‐effectiveness of sofosbuvir (SOF)‐based triple therapy (TT) compared with boceprevir (BOC)‐ and telaprevir (TVR)‐based TT in untreated genotype 1 (G1) chronic hepatitis C (CHC) patients discriminated according to IL28B genotype, severity of liver fibrosis, and G1 subtype. The available published literature provided the data source. The target population was made up of untreated Caucasian patients, aged 50 years, with G1CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euros at 2013 value), life‐years gained (LYG), quality‐adjusted life year (QALY), and incremental cost‐effectiveness ratio (ICER). Cost of SOF was assumed to be €3,500 per week, i.e., the price generating a willingness‐to‐pay threshold of €25,000 per LYG compared with TVR in the entire population of untreated G1 patients. The robustness of the results was evaluated by one‐way deterministic and multivariate probabilistic sensitivity analyses. SOF was cost‐effective compared with BOC in all strategies with the exception of cirrhosis and IL28B CC patients. In comparison with TVR‐based strategies, SOF was cost‐effective in IL28B CT/TT (ICER per LYG €22,229) and G1a (€19,359) patients, not cost‐effective in IL28B CC (€45,330), fibrosis F0‐F3 (€26,444), and in cirrhosis (€34,906) patients, and dominated in G1b patients. The models were sensitive to SOF prices and to likelihood of sustained virological response. Conclusion: In untreated G1 CHC patients, SOF‐based TT may be a cost‐effective alternative to first‐generation protease inhibitors depending on pricing. The cost‐effectiveness of SOF improved in IL28B CT/TT and G1a patients. SOF was dominated by TVR in G1b patients even if, in clinical practice, this issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration. (Hepatology 2014;59:1692–1705)

Meta-Analysis of the Placebo Rates of Clinical Relapse and Severe Endoscopic Recurrence in Postoperative Crohn's Disease

BACKGROUNDS & AIMS The benefit of therapy for prevention of postoperative recurrence of Crohns disease (CD) is limited. Clinical relapse and severe endoscopic recurrence are the main outcomes in the evaluation of trials on prevention of recurrence. The aim of this meta-analysis was to focus on knowledge of the placebo rates of relapse and recurrence in postoperative CD and to identify factors influencing these rates. METHODS We performed a meta-analysis of placebo-controlled, randomized clinical trials, evaluating therapies for postoperative maintenance of CD identified on MEDLINE from 1990 to 2006. Primary outcomes were clinical relapse and severe endoscopic recurrence. RESULTS The pooled estimate of the placebo relapse rate was 23.7% (95% confidence interval [CI], 13-35; range 0-78). There was a statistically significant heterogeneity among studies (P < .0001). Heterogeneity in clinical relapse was present even if the trials were stratified according to the time of outcome. The pooled estimate of the severe endoscopic recurrence rate was 50.2% (95% CI, 28-73; range, 30-79). There was significant heterogeneity among the studies (P = .00038). This heterogeneity was less apparent in studies carried out within 12 months. The logistic analysis identified only duration of follow-up as a variable associated with different placebo relapse rates. No variable was identified as a predictor of a placebo endoscopic recurrence rate. CONCLUSIONS There is significant heterogeneity among placebo rates in postoperative CD. No single design variable was identified that explained the heterogeneity in placebo outcomes for clinical or endoscopic recurrence.

Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma

The purpose was to assess the cost‐effectiveness of sorafenib in the treatment of hepatocellular carcinoma (HCC) patients incorporating current prices and the results of the recent published field practice SOraFenib Italian Assessment (SOFIA) study. We created a Markov Decision Model to evaluate, in a hypothetical cohort of Caucasian male patients, aged 67 years with Barcelona Clinic Liver Cancer (BCLC) C HCC, or BCLC B HCC who were unfit or failed to respond to locoregional therapies, well compensated cirrhosis, and with performance status 0‐1 according to Eastern Cooperative Oncology Group (ECOG), the cost‐effectiveness of the following strategies: (1) full or dose‐adjusted sorafenib for BCLC B and C patients together; (2) full or dose‐adjusted sorafenib for BCLC B patients; (3) full or dose‐adjusted sorafenib for BCLC C patients. Outcomes include quality‐adjusted life years (QALYs), costs, and incremental cost‐effectiveness ratio (ICER). In the base‐case analysis dose‐adjusted sorafenib was the most effective of the evaluated strategies. For dose‐adjusted sorafenib, QALY was 0.44 for BCLC B and C patients together, 0.44 for BCLC C patients, and 0.38 for BCLC B patients. The ICER of dose‐adjusted sorafenib compared with BSC was €34,534 per QALY gained for BCLC B and C patients together, €27,916 per QALY gained for BCLC C patients, and €54,881 per QALY gained for BCLC B patients. Results were sensitive to BSC survival rate, and sorafenib treatment duration. Conclusion: In daily practice dose‐adjusted, but not full‐dose, sorafenib is a cost‐effective treatment compared to BSC in intermediate and advanced HCC. (HEPATOLOGY 2013)

Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study

Objective The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. Design Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. Results Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54–82 days (n=20), 83–110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). Conclusions The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. Trial registration number ClinicalTrials.gov Identifier: NCT01657695.

Predicting survival in patients with hepatocellular carcinoma treated by transarterial chemoembolisation

Aliment Pharmacol Ther 2011; 34: 196–204

Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy

Summary.  In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir ≥ F2) is variable. Constitutional and liver disease‐related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)‐RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy‐six of 286 (26.6%) had stage ≥F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage