Patients with advanced hepatocellular carcinoma need a personalized management: A lesson from clinical practice.

The Barcelona Clinic Liver Cancer (BCLC) advanced stage (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population, where sorafenib alone is the recommended treatment. In this study, our aim was to assess treatment and overall survival (OS) of BCLC C patients subclassified according to clinical features (performance status [PS], macrovascular invasion [MVI], extrahepatic spread [EHS] or MVI + EHS) determining their allocation to this stage. From the Italian Liver Cancer database, we analyzed 835 consecutive BCLC C patients diagnosed between 2008 and 2014. Patients were subclassified as: PS1 alone (n = 385; 46.1%), PS2 alone (n = 146; 17.5%), MVI (n = 224; 26.8%), EHS (n = 51; 6.1%), and MVI + EHS (n = 29; 3.5%). MVI, EHS, and MVI + EHS patients had larger and multifocal/massive HCCs and higher alpha-fetoprotein (AFP) levels than PS1 and PS2 patients. Median OS significantly declined from PS1 (38.6 months) to PS2 (22.3 months), EHS (11.2 months), MVI (8.2 months), and MVI + EHS (3.1 months; P < 0.001). Among MVI patients, OS was longer in those with peripheral than with central (portal trunk) MVI (11.2 vs. 7.1 months; P = 0.005). The most frequent treatments were: curative approaches in PS1 (39.7%), supportive therapy in PS2 (41.8%), sorafenib in MVI (39.3%) and EHS (37.3%), and best supportive care in MVI + EHS patients (51.7%). Independent prognostic factors were: Model for End-stage Liver Disease score, Child-Pugh class, ascites, platelet count, albumin, tumor size, MVI, EHS, AFP levels, and treatment type. CONCLUSION: BCLC C stage does not identify patients homogeneous enough to be allocated to a single stage. PS1 alone is not sufficient to include a patient into this stage. The remaining patients should be subclassified according to PS and tumor features, and new patient-tailored therapeutic indications are needed. (Hepatology 2018;67:1784-1796).

Restaging Patients With Hepatocellular Carcinoma Before Additional Treatment Decisions: A Multicenter Cohort Study.

Prognostic assessment of patients with hepatocellular carcinoma (HCC) at the time of diagnosis remains controversial and becomes even more complex at the time of restaging when new variables need to be considered. The aim of the current study was to evaluate the prognostic utility of restaging patients before proceeding with additional therapies for HCC. Two independent Italian prospective databases were used to identify 1,196 (training cohort) and 648 (validation cohort) consecutive patients with HCC treated over the same study period (2008-2015) who had complete restaging before decisions about additional therapies. The performance of the Italian Liver Cancer (ITA.LI.CA) prognostic score at restaging was compared with that of the Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, and Cancer of the Liver Italian Program systems. A multivariable Cox survival analysis was performed to identify baseline, restaging, or dynamic variables that were able to improve the predictive performance of the prognostic systems. At restaging, 35.3% of patients maintained stable disease; most patients were either down-staged by treatment (27.2%) or had disease progression (37.5%). The ITA.LI.CA scoring system at restaging demonstrated the best prognostic performance in both the training and validation cohorts (c-index 0.707 and 0.722, respectively) among all systems examined. On multivariable analysis, several variables improved the prognostic ability of the ITA.LI.CA score at restaging, including progressive disease after the first treatment, Model for End-Stage Liver Disease at restaging, and choice of nonsurgical treatment as additional therapy. A new ITA.LI.CA restaging model was created that demonstrated high discriminative power in both the training and validation cohorts (c-index 0.753 and 0.745, respectively). CONCLUSION: Although the ITA.LI.CA score demonstrated the best prognostic performance at restaging, other variables should be considered to improve the prognostic assessment of patients at the time of deciding additional therapies for HCC.

The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: A multicenter cohort study.

BACKGROUND: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients. PATIENTS AND METHODS: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival. RESULTS: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT = 0.19 (0.18-0.20); RES = 0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT = 0.58 (0.55-0.61); SOR = 0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage. CONCLUSION: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage.

Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma.

BACKGROUND & AIMS: Assessment of long-term outcome is required in hepatitis C virus (HCV)-infected patients with cirrhosis, who have been successfully treated for Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC). However, problems arise due to the lack of models accounting for early changes during follow-up. The aim of this study was to estimate the impact of early events (HCC recurrence or hepatic decompensation within 12months of complete radiological response) on 5-year overall survival (OS) in a large cohort of patients with HCV and cirrhosis, successfully treated HCC. METHODS: A total of 328 consecutive Caucasian patients with HCV-related cirrhosis and BCLC stage 0/A HCC who had complete radiological response after curative resection or thermal ablation were prospectively recruited to this study. Primary endpoint of the study was 5-year OS. Independent baseline and time-dependent predictors of 5-year OS were identified by Cox model. RESULTS: The observed 5-year survival rate was 44%. The observed HCC early recurrence and early hepatic decompensation rate were 21% and 10%, respectively. Early hepatic decompensation (Hazard Ratio [HR] 7.52; 95% confidence intervals (CI): 1.23-13.48) and HCC early recurrence as time-dependent covariates (HR 2.50; 95%CI: 1.23-5.05), presence of esophageal varices at baseline (HR 1.66; 95% CI: 1.02-2.70) and age (HR 1.04; 95% CI: 1.02-1.07) were significantly associated with the 5-year OS. CONCLUSION: Survival in HCV-infected patients with cirrhosis and successfully treated HCC is influenced by early hepatic decompensation. Our study indirectly suggests that direct-acting antiviral agents could improve OS of HCC patients through long-term preservation of liver function, resulting in a lower cirrhosis-related mortality and a greater change of receiving curative treatments. LAY SUMMARY: Survival in hepatitis C virus (HCV) infected patients with cirrhosis and successfully treated hepatocellular carcinoma (HCC), is mainly influenced by early hepatic decompensation. HCV eradication after treatment with new direct-acting antiviral agents could improve overall survival of HCC patients through long-term preservation of liver function.

The evolutionary scenario of hepatocellular carcinoma in Italy: an update.

BACKGROUND & AIMS: Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of aetiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. METHODS: Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centres from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). RESULTS: The main results were as follows: (i) progressive patient aging; (ii) progressive expansion of non-viral cases and, namely, of "metabolic" hepatocellular carcinomas; (iii) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semi-annual) surveillance programme; (iv) favourable cancer stage migration; (v) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early- or intermediate-stage hepatocellular carcinoma. CONCLUSIONS: During the last 15 years several aetiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was owing both to the wider use of semi-annual surveillance, expanding the proportion of tumours that qualified for curative treatments, and to the improved outcome of loco-regional treatments.

Prognosis of untreated hepatocellular carcinoma.

UNLABELLED: The prognosis of untreated patients with hepatocellular carcinoma (HCC) is heterogeneous, and survival data were mainly obtained from control arms of randomized studies. Clinical practice data on this topic are urgently needed, so as to help plan studies and counsel patients. We assessed the prognosis of 600 untreated patients with HCC managed by the Italian Liver Cancer Group. Prognosis was evaluated by subdividing patients according to the Barcelona Clinic Liver Cancer (BCLC) classification. We also assessed the main demographic, clinical, and oncological determinants of survival in the subgroup of patients with advanced HCC (BCLC C). Advanced (BCLC C: n = 138; 23.0%) and end-stage HCC (BCLC D; n = 210; 35.0%) represented the majority of patients. Overall median survival was 9 months, and the principal cause of death was tumor progression (n = 279; 46.5%). Patients' median survival progressively and significantly decreased as BCLC stage worsened (BCLC 0: 38 months; BCLC A: 25 months; BCLC B: 10 months; BCLC C: 7 months; BCLC D: 6 months; P < 0.0001). Female gender (hazard ratio [HR] = 0.55; 95% confidence interval [CI] = 0.33-0.90; P = 0.018), ascites (HR = 1.81; 95% CI = 1.21-2.71; P = 0.004), and multinodular (>3) HCC (HR = 1.79; 95% CI = 1.21-2.63; P = 0.003) were independent predictors of survival in patients with advanced HCC (BCLC C). CONCLUSION: BCLC adequately predicts the prognosis of untreated HCC patients. In untreated patients with advanced HCC, female gender, clinical decompensation of cirrhosis, and multinodular tumor are independent prognostic predictors and should be taken into account for patient stratification in future therapeutic studies.

BCLC stage B hepatocellular carcinoma and transcatheter arterial chemoembolization: a 20-year survey by the Italian Liver Cancer group.

BACKGROUND & AIMS: Significant proportion of Hepatocellular Carcinoma (HCC) cases are diagnosed in stage B of Barcelona Clinic Liver Cancer (BCLC) algorithm, in which the standard of care is Transcatheter Arterial ChemoEmbolization (TACE). We aimed to ascertain adherence to current guidelines, survival and prognostic factors in BCLC stage B patients. METHODS: From 3027 HCC cases recruited from 1986 to 2008 by the Italian Liver Cancer group (2430 with data allowing a correct allocation in the BCLC system), a retrospective analysis was conducted on those diagnosed in BCLC stage B (405 patients, 17%). Statistics were performed with Kaplan-Meier (log rank) method and Cox multivariate analysis. RESULTS: Median overall survival in BCLC stage B patients was 25 months (Confidence Interval - C.I. - 22-28 months) with a 5-year survival of 18%. Child-Pugh class, oesophageal varices and Alpha-foetoprotein (AFP) were the independent predictors of survival. TACE was applied in 40% of cases and did not offer the longest survival in comparison with surgical or percutaneous treatments (median 27 months vs. 37 and 36 months, respectively) (P < 0.001). BCLC stage B patients undergoing radical treatments were more frequently in Child-Pugh class A and had a significantly lower number of lesions; patients undergoing best supportive care were frequently in Child-Pugh class B and had a multifocal disease. Survival after TACE did not significantly increase over time. CONCLUSIONS: In clinical practice, TACE cannot be considered the best approach for BCLC stage B patients who represent a heterogeneous population and are often suitable for more aggressive therapies, which lead to a better survival.

Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND & AIMS: Ultrasound surveillance does not detect early stage hepatocellular carcinomas (HCCs) in some patients with cirrhosis, although the reasons for this have not been well studied. We assessed the rate at which ultrasound fails to detect early stage HCCs and factors that affect its performance. METHODS: We collected information on 1170 consecutive patients included in the Italian Liver Cancer (ITA.LI.CA) database who had Child-Pugh A or B cirrhosis and were diagnosed with HCC during semiannual or annual ultrasound surveillance, from January 1987 through December 2008. Etiologies included hepatitis C virus infection (59.3%), alcohol abuse (11.3%), hepatitis B virus infection (9%), a combination of factors (15.6%), and other factors (4.7%). Surveillance was considered to be a failure when patients were diagnosed with HCC at a stage beyond the Milan criteria (1 nodule ≤5 cm or ≤3 nodules each ≤3 cm). RESULTS: HCC was found beyond Milan criteria in 34.3% of surveilled patients (32.2% during semi-annual surveillance and 41.3% during annual surveillance; P < .01). Nearly half of surveillance failures were associated with at least one indicator of aggressive HCC (levels of AFP >1000 ng/mL, infiltrating tumors, or vascular invasion and metastases). Semiannual surveillance, female sex, Child-Pugh class A, and α-fetoprotein levels of 200 ng/mL or less were associated independently with successful ultrasound screening for HCC. CONCLUSIONS: Based on our analysis of surveillance for HCC in patients with cirrhosis, the efficacy of ultrasound-based screening is acceptable. Ultrasound was least effective in identifying aggressive HCC, and at surveillance intervals of more than 6 months.

Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis.

UNLABELLED: Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child-Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC ≤ 3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal ≤ 20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC ≤ 2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. CONCLUSION: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent.

Influence of clinically significant portal hypertension on survival after hepatic resection for hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: The role of clinically significant portal hypertension on the prognosis of cirrhotic patients undergoing hepatic resection for hepatocellular carcinoma (HCC) is debated. AIMS: In this study, our aim was to assess the role of clinically significant portal hypertension after hepatic resection for HCC in patients with cirrhosis. METHODS: We assessed the prognostic role of the presence of clinically significant portal hypertension (oesophageal/gastric varices/portal hypertensive gastropathy or a platelet count <100 × 10(9) /L associated with splenomegaly) in 152 patients with compensated cirrhosis who underwent hepatic resection for HCC at the Italian Liver Cancer centres. Survival rates were assessed in the whole series, in the subgroup of Child-Pugh score 5 patients with uninodular HCC ≤ 5 cm, and in Child-Pugh score 5 patients with uninodular HCC ≤ 2 cm and normal bilirubin. RESULTS: Median survival was similar in patients with and without clinically significant portal hypertension (79 vs 77 months, P = 0.686). Child-Pugh score 5 was the only variable significantly associated with survival by Cox multiple regression (P = 0.007). In Child-Pugh score 5 patients with single HCC ≤ 5 cm or in those with single HCC ≤ 2 cm and normal bilirubin, there was no survival difference between patients with and without clinically significant portal hypertension (median survival: 94 vs 78 months, P = 0.121 and >100 vs 86 months, P = 0.742). CONCLUSIONS: Presence of clinically significant portal hypertension has no influence on survival of patients with well-compensated cirrhosis undergoing hepatic resection for HCC.

Rise and fall of HCV-related hepatocellular carcinoma in Italy: a long-term survey from the ITA.LI.CA centres.

BACKGROUND & AIMS: Hepatitis C virus (HCV) is the leading aetiological factor of HCC in the western world where, overall, its incidence is increasing, despite data suggesting an initial drop in some areas. The aim of this study was to evaluate epidemiology, clinical features and survival of HCV-related HCC (HCV-HCC) in a wide time range in Italy. METHODS: Multicentre retrospective study including 3695 patients prospectively recruited by the ITA.LI.CA group. Patients were classified into three subgroups according to aetiology (Group A[GA], pure HCV; Group B[GB], HCV + cofactors; and Group C[GC], non-HCV) and in 5 time cohorts (5 years each), according to the year of diagnosis. Age, gender, Child-Pugh score, modality of diagnosis, stage, presence of thrombosis/metastases, type of treatment and survival were analysed. RESULTS: A total of 1801 GA patients, 445 GB and 1333 GC were recruited. The number of GA patients peaked in the 1996-2000, gradually dropping thereafter (P < 0.0001), as observed for GB (P < 0.0001). Age at diagnosis increased (P < 0.0001), while percentage of patients diagnosed during surveillance and stage improved only in GA (P = 0.02 and P = 0.003 respectively). The survival significantly increased over time particularly in GA (median 37 months) and was longer in GA than in GB and GC (P < 0.0001). CONCLUSIONS: The prevalence of HCC-HCV is decreasing in Italy since 2001. HCV-HCC patients are older, more frequently diagnosed under surveillance and in an earlier stage. HCC survival improved in the last 15 years and is significantly higher in patients with HCV-HCC. We therefore expect a further drop in both incidence and mortality for HCV-HCC in the years to come.

Cost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian Liver Cancer population.

BACKGROUND & AIMS: It was recently shown that semi-annual surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients provides a prognostic advantage over the annual program; however, its cost-effectiveness (CE) in the general cirrhotic population still needs to be defined. METHODS: A Markov model was built to compare CE of these two strategies, considering literature results and treatment modalities of 918 cirrhotic patients from the Italian Liver Cancer (ITA.LI.CA) database. RESULTS: Results from the Markov model suggest that, compared to annual surveillance, semi-annual surveillance leads to a gain in quality-adjusted life expectancy, in an unselected cirrhotic population, of 1.35 quality-adjusted life-months (QALMs) over 10 years since surveillance start in compensated patients, and of 0.73 QALMs in decompensated patients. Semi-annual surveillance was more cost-effective in compensated than in decompensated cirrhosis, with an incremental CE ratio (ICER) of 1997 and 3814€/QALM, respectively. In compensated cirrhosis, semi-annual surveillance was more cost-effective than the annual program when the annual HCC incidence was ≥3.2% and the relative survival gain after cancer diagnosis was ≥20% with respect to the annual program. In decompensated cirrhosis, semi-annual surveillance was cost-effective in patients amenable to liver transplantation. In both groups, CE of semi-annual surveillance improved with the increase of annual incidence and the survival benefit obtainable with HCC treatment. CONCLUSIONS: Both surveillance strategies for HCC in cirrhotic patients can be recommended, according to the individual risk profile for HCC occurrence and the expected survival gain obtainable after tumor diagnosis and therapy.

The changing scenario of hepatocellular carcinoma over the last two decades in Italy.

BACKGROUND & AIMS: This study investigates whether the aetiologic changes in liver disease and the improved management of hepatocellular carcinoma (HCC) have modified the clinical scenario of this tumour over the last 20 years in Italy. METHODS: Retrospective study based on the analysis of the ITA.LI.CA (Italian Liver Cancer) database including 3027 HCC patients managed in 11 centres. Patients were divided into 3 groups according to the period of HCC diagnosis: 1987-1996 (year of the "Milano criteria" publication), 1997-2001 (year of release of the EASL guidelines for HCC), and 2002-2008. RESULTS: The significant changes were: (1) progressive patient ageing; (2) increasing prevalence of HCV infection until 2001, with a subsequent decrease, when the alcoholic aetiology increased; (3) liver function improvement, until 2001; (4) increasing "incidental" at the expense of "symptomatic" diagnoses, until 2001; (5) unchanged prevalence of tumours diagnosed during surveillance (around 50%), with an increasing use of the 6-month schedule; (6) favourable HCC "stage migration", until 2001; (7) increasing use of percutaneous ablation; (8) improving survival, until 2001. CONCLUSIONS: Over the last 20 years, several aetiologic and clinical features regarding HCC have changed. The survival improvement observed until 2001 was due to an increasing number of tumours diagnosed in early stages and in a background of compensated cirrhosis, and a growing and better use of locoregional treatments. However, the prevalence of early cancers and survival did not increase further in the last years, a result inciting national policies aimed at implementing surveillance programmes for at risk patients.

Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study.

BACKGROUND: Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. METHODS: A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient's 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. FINDINGS: 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B-C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1.530 (95% CI 1.107-2.116) for BCLC A versus BCLC 0, 1.572 (1.350-1.830) for BCLC B-C versus BCLC A, and 1.470 (1.164-1.856) for BCLC D versus BCLC B-C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11.19 months (IQR 10.73-11.67) for BCLC 0, 13.49 months (11.51-15.57) for BCLC A, 17.36 months (15.06-19.28) for BCLC B-C, and 28.46 months (26.38-30.34) for BCLC D. INTERPRETATION: Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B-C), regardless of the nodule number-size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. FUNDING: None.

Relative decrease in the role played by hepatitis B virus infection in the aetiology of hepatocellular carcinoma during a 20-year period: a multicentre Italian study.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is one of the most frequent aetiological factors associated with the development of hepatocellular carcinoma (HCC). AIM: This study evaluated the temporal trend in the aetiological role played by HBV infection alone in patients diagnosed with HCC during the last 20 years in Italy. METHODS: Among the 2042 HCC patients included in the Italian Liver Cancer (ITA.LI.CA.) database, 346 had chronic HBV infection alone. We assessed the proportion of HCC patients with HBV infection in four quinquennia (1987-1991, 1992-1996, 1997-2001, 2002-2006) and evaluated their main clinical, virological and oncological characteristics across these periods. RESULTS: Although the absolute number increased, the proportion of HBV-related HCC relatively decreased over time from 26.7% (47/176 patients) in 1987-1991 to 14.7% (127/862 patients) in 2002-2006 (P=0.0005). Patients' demographical, clinical and virological characteristics were similar across the four quinquennia. A greater proportion of patients was diagnosed with non-advanced HCC in more recent years (from 26% in 1987-1991 to 48% in 2002-2006, P=0.025), likely owing to a growing use of semiannual surveillance (from 63% in 1987-1991 to 80% in 2002-2006). CONCLUSIONS: We observed a significant, relative decrease in the role played by chronic HBV infection alone in the determinism of HCC during the last 20 years. In recent years, more patients are diagnosed with non-advanced HCC probably owing to improvements in HCC detection.

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience.

OBJECTIVES: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (>or=70 years) and younger patients (<70 years). DESIGN: Multicentre retrospective cohort study and nested case-control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. RESULTS: Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. CONCLUSIONS: The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

Role of Transient Elastography to Stage Fontan-Associated Liver Disease (FALD) in Adults with Single Ventricle Congenital Heart Disease Correction.

Fontan-associated liver disease (FALD) is an arising clinical entity that can occur long after a successful Fontan operation for correction of single ventricle (SV) congenital heart disease (CHD). Occurrence of FALD is characterized by liver cirrhosis and other hepatic complications, and determinates an increased morbidity and mortality. Currently, there is no consensus on how to stage FALD. We report here our experience by an observational study in 52 patients with SV-CHD after Fontan operation that were recruited through a period of 36 ± 9.3 months. All cases underwent lab tests and liver and cardiac imaging evaluation, including liver stiffness (LS) measurement by transient elastography (TE) (FibroScan®). According to selective criteria for liver disease, we identified 23/43 (53.5%) cases with advanced FALD that showed: older age (p < 0.05), larger hepatic and cava veins diameter (p < 0.05), worsened NYHA class (p < 0.05), abnormal lymphocytes (p < 0.01), platelet count (p < 0.05), and GGT, prothrombin time (INR), albumin and cystatin C levels (p < 0.05), with respect to cases without advanced FALD. LS values were significantly increased in cases with advanced FALD, at cut-off values higher than 22 kPa (p < 0.001). LS, and its combined score with spleen diameter and platelet count (LSPS) successfully helped to detect 100% of cases with portal hypertension (p < 0.001). In conclusion, LS can be effective to stage FALD and to uncover cases with severe risk of complications, avoiding higher morbidity and mortality related to advanced FALD.

Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival.

BACKGROUND & AIMS: The current guidelines recommend the surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on liver ultrasonography repetition at either 6 or 12 month intervals, since there is no compelling evidence of superiority of the more stringent program. This study aimed at comparing cancer stage, treatment applicability, and survival between patients on semiannual or annual surveillance. METHODS: We analyzed the clinical records of 649 HCC patients in Child-Pugh class A or B, observed in ITA.LI.CA centers. HCC was detected in 510 patients submitted to semiannual surveillance (Group 1) and in 139 submitted to annual surveillance (Group 2). In Group 1 the survival was presented as observed and corrected for the lead time. RESULTS: The cancer stage was less severe in Group 1 than in Group 2 (p<0.001), with more single tiny (2 cm) and less advanced tumors. Treatment applicability was improved by the semiannual program (p=0.020). The median observed survival was 45 months (95% CI 40.0-50.0) in Group 1 and 30 months (95% CI 24.0-36.0) in Group 2 (p=0.001). The median corrected survival of Group 1 was 40.3 months (95% CI 34.9-45.7) (p=0.028 with respect to the observed survival of Group 2). Age, platelet count, alpha-fetoprotein, Child-Pugh class, cancer stage, and hepatocellular carcinoma treatment were independent prognostic factors. CONCLUSIONS: Semiannual surveillance increases the detection rate of very early hepatocellular carcinomas and reduces the number of advanced tumors as compared to the annual program. This translates into a greater applicability of effective treatments and into a better prognosis.

Hepatocellular carcinoma in patients with cryptogenic cirrhosis.

BACKGROUND & AIMS: Patients with cryptogenic cirrhosis (CC) can develop hepatocellular carcinoma (HCC), although the clinical characteristics of HCC in these patients have not been completely defined. We aimed to characterize the clinical features of patients diagnosed with HCC after CC during a 15-year period (1992-2006). METHODS: The clinical characteristics of 45 consecutive CC patients with HCC were analyzed, along with modality of diagnosis, tumor stage, treatment, survival, and causes of death. Data were compared with those of 426 consecutive patients with HCC and only hepatitis C virus (HCV) infection, diagnosed during the same period at the Italian Liver Cancer group centers. RESULTS: HCC patients with CC had similar impairments in liver function as patients with HCV infection (Child-Pugh class A: 53% vs 65%; P = .141). However, the HCC patients with CC had lower aminotransferase levels (P < .001) and higher platelet counts (P < .001). HCC was significantly less likely to be diagnosed during surveillance in CC patients (29% vs 64%; P < .0001). Patients with CC had a significantly greater prevalence of advanced HCC stage, according to Milano criteria (69% vs 41%; P < .0005), larger HCC size (4.9 vs 3.0 cm; P = .0001), lower amenability to any treatment (27% vs 42%; P = .036), and shorter survival times (P = .009, log-rank test) compared with HCV patients. Causes of death were similar in the 2 groups. CONCLUSIONS: Compared with HCV patients, HCC in CC patients often is diagnosed at an advanced stage, probably owing to lack of surveillance; this leads to limited treatment options and shorter survival times.

Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population.

The presence of cirrhosis is the only risk factor that is advocated for recurrence of hepatocellular carcinoma (HCC) 2 years after hepatic resection compared with noncirrhotic control subjects; however, data for cohorts of exclusively patients with cirrhosis are lacking. This study was designed to assess risk factors and annual incidence of early (<2 years) and late (>2 years) recurrence after resection of cirrhosis and to compare these findings with those of patients with cirrhosis enrolled in HCC surveillance programs (HCC occurrence). Data from 204 patients with cirrhosis resected for HCC and 150 surveilled for cirrhosis were retrospectively collected and compared using propensity score matching to overcome biases of nonrandomized study. Risk factors for early recurrence (incidence = 21.8%/year) were higher serum alpha-fetoprotein (AFP) levels, poorly differentiated tumor, and presence of microvascular invasion (P < 0.05). Risk factors for both late recurrence (18.4%/year) and HCC occurrence (3.3%/year) were male gender, older age, and higher serum transaminase levels; multiple primary tumors and higher AFP were additional risk factors for late recurrence and HCC occurrence respectively (P < 0.05). After propensity adjustment, resected patients with less than two risk factors for late recurrence showed an annual incidence of HCC (6.2%/year) similar to that of surveilled patients with > or =2 risk factors (5.8%/year; P = 0.898). Early and late recurrence of HCC for patients with cirrhosis after resection have distinct risk factors. Annual incidence of HCC 2 years or more after resection may be similar to that of general patients because the same risk factors are involved; assessment of these characteristics could be useful in tailoring clinical management.