Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease.

Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.

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.

Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC).

BACKGROUND AND AIM: The serpin squamous cell carcinoma antigen complexed with IgM (SCCA-IgM) has been reported as a promising serological marker for hepatocellular carcinoma (HCC). We aimed to further evaluate SCCA-IgM diagnostic accuracy and to determine its prognostic role. METHODS: SCCA-IgM levels were determined in 327 sera obtained from 81 HCC patients, 206 cirrhotics and 40 healthy blood donors (controls). Sensitivity, specificity, correlation with clinical and tumor parameters and with survival were evaluated. RESULTS: HCC patients had SCCA-IgM levels significantly higher than controls and cirrhotics (P < 0.0001). Sensitivity, specificity, positive and negative predictive values for HCC were 89%, 50%, 41% and 92%, respectively. In comparison, sensitivity and specificity for alphafetoprotein were 48% and 85%. SCCA-IgM levels were not significantly correlated with clinical or biological variables. With a cut-off of 130 AU/mL (receiver operating characteristic curves), SCCA-IgM proved efficient in the prediction of prognosis, identifying the patients with long overall survival (efficiency validated in the homogenous subgroup of patients with intermediate-stage HCC undergoing transarterial chemoembolization) and predicting progression-free survival. A Cox multivariate analysis confirmed SCCA-IgM predictive value, identifying tumor size and SCCA-IgM levels as independent predictors of survival. A reduction in SCCA-IgM levels correlated with response to treatment. CONCLUSIONS: SCCA-IgM is a sensitive marker of HCC in patients with cirrhosis even though lacking in specificity. The determination of the levels of the marker in HCC patients is highly efficient in predicting the patients' prognosis, identifying those with long overall and progression-free survival and the responders and should be introduced in the clinical practice.

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.

Circulating free DNA in the progression of liver damage to hepatocellular carcinoma.

PURPOSE: Circulating free DNA (cfDNA) is an extracellular DNA released in the blood by tumor apoptotic/necrotic cells. cfDNA determination has been proposed as a non-invasive and sensitive marker in the diagnosis of cancer. Our aim was to validate the quantification of cfDNA as a diagnostic and prognostic tool in hepatocellular carcinoma (HCC). METHODS: cfDNA was quantified by real-time PCR amplification of the hTERT gene in 142 plasma samples obtained from 66 patients with HCC, 35 with cirrhosis (CIRR) and 41 with advanced HCV-related chronic hepatitis (CH). RESULTS: cfDNA was documented in the plasma of 22 % of the CH patients, 57 % of those with CIRR and 61 % of HCC patients. Its concentration was lower in CH with respect to CIRR and HCC (p = 0.02). A cutoff value in the diagnosis of HCC was calculated by the ROC method (area under the curve 0.69, 91 % sensitivity, 43 % specificity) considering HCC versus CH/CIRR, taken together. Patients with multinodular HCC showed significantly higher levels of cfDNA (p = 0.05). A cutoff value for cfDNA was also calculated for discriminating patients with long or short survival. Survival was significantly longer in patients with cfDNA below than in those above the cutoff value (37 vs. 24 months, p = 0.03). Similar results were obtained in the subgroups of patients with viral or with HCV-only etiology, with slightly higher overall diagnostic accuracy. CONCLUSIONS: The role of the quantitative analysis of cfDNA as a diagnostic test is debatable, but cfDNA levels discriminate patients with more advanced stages of disease, demonstrating a prognostic relevance in patients with HCC.

Molecular targeted therapy in hepatocellular carcinoma: present achievements and future challenges.

Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib's role and safety profile, especially in the treatment of patients with suboptimal liver function.

Liver transplantation for hepatocellular carcinoma in clinical practice: the lesson from a 20-year multicentre experience in Italy.

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. AIMS: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. METHODS: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival. RESULTS: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival. CONCLUSION: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited.

Hepatitis B virus-related hepatocellular carcinoma: primary, secondary, and tertiary prevention.

With respect to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), primary, secondary, and tertiary prevention measures have been or should be adopted. In primary prevention, behavioral patterns represent an important risk factor for HBV infection and should be controlled, discouraging those favoring infection. Interferon treatment shows a modest effect in reducing HCC risk in treated patients, but the data obtained cannot be converted in clinical practice. Nucleoside analogs significantly reduce, but do not abolish, HCC risk in patients with cirrhosis, and should therefore be used in patients with cirrhosis and also to diminish the risk of the other potential complications. With respect to secondary prevention, surveillance with semiannual ultrasound examination is indicated in patients with HBV-related cirrhosis as well as in other subgroups of patients, depending on racial and geographical pattern. Finally, the role of interferon in tertiary prevention of HCC relapse after radical treatment is still under debate; some evidence in favor of the treatment is present, but side effects due to toxicity are frequent and severe enough to limit patients' compliance substantially. As there is definitely no agreement on the efficacy and cost-effectiveness of antiviral treatment in HCC prevention, there is still a need for well-constructed, large size, and randomized prospective trials to confirm what is still required based on expert opinion rather than on sound scientific evidence.

Megestrol and embryonic extracts in the treatment of advanced hepatocellular carcinoma: A prospective randomized trial in the pre-sorafenib era.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) achieved significant results by the new treatment with sorafenib (a multi-tyrosine kinase inhibitor), but, because it has been tested mainly in Child A cirrhosis, patients with impaired liver function are not eligible for the treatment. METHODS: This study was an open label phase III randomized trial comparing Synchro-Levels (Alphrema, Varese, Italy) and megestrol, with a 2:1 design, in patients with advanced HCC, planned before the sorafenib registration. End-points were objective response and impact on performance status (primary) and biochemical response (secondary). RESULTS: The patients enrolled were 61 (43 men, 18 women; Child A in 28 [48%] and B in 33 [52%]). Forty-three were assigned to Synchro-Levels, 18 to megestrol. Most patients had multifocal disease (75% in megestrol and 59% in Synchro-Levels) and there was a significant difference in tumor burden, with more advanced disease in the megestrol arm (P = 0.0002). At 3 months, tumor burden was more frequently stable with megestrol, while performance status was significantly better in patients treated with Synchro-Levels. At 6 months, alpha-fetoprotein was more frequently stable or reduced with megestrol. An objective response was observed in a megestrol-treated patient. Mortality was significantly lower and long-term survival significantly more frequent with megestrol. CONCLUSION: Megestrol treatment shows good results in advanced HCC and could become part of best supportive care in patients not suitable for other treatments, that, despite sorafenib, remain an important share.