Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available ...on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD‐related HCC (NAFLD‐HCC) and to compare them to those of hepatitis C virus (HCV)‐related HCC. A total of 756 patients with either NAFLD (145) or HCV‐related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead‐time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD‐HCC patients, in contrast to the near totality of HCV‐HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD‐HCC, 25.5 months (95% confidence interval 21.9‐29.1), than in those with HCV‐HCC, 33.7 months (95% confidence interval 31.9‐35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD‐HCC and HCV‐HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD‐HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827–838)
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, α-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.
The clinical usefulness of alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC) management is debatable.
To assess, in a large multi-centric survey, diagnostic and prognostic reliability of AFP, ...predictive factors, and any correlation with the tumor immunophenotype.
A total of 1,158 patients with HCC were analyzed with reference to serum AFP levels at diagnosis. We evaluated: HCC grading, histotype, and size; Okuda, tumor-nodes-metastases (TNM), and Child-Pugh scores; liver function, symptoms, presence of metastases or portal thrombosis, etiology, survival, and treatment. In 66 patients with histological diagnosis, the pathologists evaluated p53 overexpression, MIB 1 labeling index, BCL-2 positive cells (index of apoptosis), and CD44 (adhesion molecule) positivity.
Patients were divided into three AFP groups: normal (<20 ng/mL) 46%, elevated (21-400 ng/mL) 36%, and diagnostic (>400 ng/mL) 18%. Statistical correlations were significant for: weight loss (p= 0.0056), pain (p= 0.0025), Child-Pugh score (p= 0.001), tumor size, Okuda's and TNM stages, metastases, thrombosis, type of treatment (all p < 0.0001), and female sex (p < 0.004). AFP correlated with survival overall, in patients untreated, transplanted, or undergoing locoregional treatments; but not in those surgically treated. In the discriminant analysis, the related variables were size, female sex, Child-Pugh score, TNM staging (steps 1-4). When using the receiver operating characteristic curve, the prognostic reliability of AFP was limited with area under the curve of 0.59. Finally, patients with low expression of BCL2 had high AFP levels (p < 0.05). AFP positively correlated with Edmonson score (p < 0.0001).
The evaluation of this large series of HCC patients allowed us to: confirm the low sensitivity (54%) of AFP in the diagnosis of HCC and its prognostic value, albeit limited, being tumor size, female sex (intriguingly enough), Child-Pugh score, and TNM staging independent predictors.
Summary 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.
A consensus on the most reliable staging system for hepatocellular carcinoma (HCC) is still lacking but the most used is a revised Barcelona Clinic Liver Cancer (BCLC) system, adopted by the American ...Association for the Study of Liver Diseases (AASLD). We investigated how many patients are diagnosed in "very early" and "early" stage, follow the AASLD guidelines for treatment and whether their survival depends on treatment.
Data were collected in 530 "very early" and "early" HCC patients recruited by a multicentric Italian collaborative group (ITA.LI.CA). The Kaplan-Meier method was used to estimate overall survival and the log rank to test the statistical significance of difference between groups. Cox's multivariate stepwise regression analysis was used to pinpoint independent prognostic factors and the adjusted relative risks (hazard ratios) were calculated as well. A statistical analysis based on the chi-square test was used to identify significant differences in clinical or pathological features between patients. A P-value < 0.05 was considered statistically significant.
"Very early" HCC were 3%; Cox multivariate analysis did not identify variables independently associated with survival. The patients following AASLD recommendations (20%) did not show longer survival. In "early" HCC patients (25%), treatment significantly modulated survival (p = 0.0001); the 28% patients treated according to the AASLD criteria survived longer (p = 0,004). The Cox analysis however identified only age, gender, number of lesions and Child class as independent predictors of survival.
patients with very early" HCC were very few in this analysis. In most instances they were not treated with the treatment suggested as the most appropriate by the AASLD guidelines and the type of treatment had no impact on survival, even though the number of patients was relatively low and part of the patients were diagnosed before the introduction of the guidelines: this analysis, therefore, might not be considered as conclusive and should be validated. The "early" stage group involved more patients, rarely treated according to the guidelines, both overall and also in those diagnosed after their publication; the survival was in part predicted by the type of treatment, with better results in those treated according to AASLD indications.
Background & Aims Lead-time is the time by which diagnosis is anticipated by screening/surveillance with respect to the symptomatic detection of a disease. Any screening program, including ...surveillance for hepatocellular carcinoma (HCC), is subject to lead-time bias. Data regarding lead-time for HCC are lacking. Aims of the present study were to calculate lead-time and to assess its impact on the benefit obtainable from the surveillance of cirrhotic patients. Methods One-thousand three-hundred and eighty Child–Pugh class A/B patients from the ITA.LI.CA database, in whom HCC was detected during semiannual surveillance (n = 850), annual surveillance (n = 234) or when patients came when symptomatic (n = 296), were selected. Lead-time was estimated by means of appropriate formulas and Monte Carlo simulation, including 1000 patients for each arm. Results The 5-year overall survival after HCC diagnosis was 32.7% in semiannually surveilled patients, 25.2% in annually surveilled patients, and 12.2% in symptomatic patients ( p <0.001). In a 10-year follow-up perspective, the median lead-time calculated for all surveilled patients was 6.5 months (7.2 for semiannual and 4.1 for annual surveillance). Lead-time bias accounted for most of the surveillance benefit until the third year of follow-up after HCC diagnosis. However, even after lead-time adjustment, semiannual surveillance maintained a survival benefit over symptomatic diagnosis (number of patients needed to screen = 13), as did annual surveillance (18 patients). Conclusions Lead-time bias is the main determinant of the short-term benefit provided by surveillance for HCC, but this benefit becomes factual in a long-term perspective, confirming the clinical utility of an anticipated diagnosis of HCC.
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. (HEPATOLOGY 2012)
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.
Surveillance of cirrhotic patients for early detection of hepatocellular carcinoma, based on ultrasonography and alpha1-fetoprotein determination, is a recommended practice. However, it has not been ...proved that this procedure can improve patient survival.
We conducted a multicenter retrospective study on 1051 consecutive patients with hepatocellular carcinoma. The criteria for eligibility were presence of underlying cirrhosis, and description of cancer stage and modalities of its diagnosis. Among 821 patients fulfilling these criteria, the tumor was detected during semiannual surveillance in 215 individuals (group 1), during annual surveillance in 155 (group 2), and as a result of symptoms or incidentally in 451 (group 3). Survival of patients under surveillance was corrected for lead time.
Cancer stage was similar in groups 1 and 2 and was less advanced than in group 3 (p < 0.001). The frequency of ablative treatments or chemoembolization was similar in groups 1 and 2 and was greater than in group 3 (p < 0.001). Both surveillance programs doubled the prevalence of potential candidates for liver transplantation (68.5% and 62.5%) with respect to group 3 (32.3%, p < 0.001). However, only 15 patients underwent transplantation. In groups 1 and 2, the 5-yr survival was equivalent and was greater than in group 3 (p < 0.001). By segregating patients according to severity of cirrhosis, the benefit was confined to compensated cirrhosis (adjusted relative risk of death for patients under surveillance: 0.59 95% CI = 0.45-0.78).
Semiannual and annual surveillance equally improve the survival of cirrhotic patients with hepatocellular carcinoma and greatly increase the amenability rate to liver transplantation. When access to liver transplantation is limited, this benefit is restricted to patients with a good cirrhosis-related prognosis.
The aim of this study was to assess whether hepatocellular carcinoma occurring in the setting of hepatitis B or C virus infection has different prognosis.
We performed a multicentric case-control ...study comparing 102 pairs of patients affected by hepatitis B virus- or hepatitis C virus-related hepatocellular carcinoma. Patients were matched for sex (male/female: 84/18 pairs), age, center, and period of enrollment, underlying chronic liver disease (cirrhosis/chronic hepatitis: 97/5 pairs), Child-Pugh class (A/B/C: 70/25/7 pairs), hepatocellular carcinoma stage (nonadvanced/advanced: 50/52 pairs) and, when possible, modality of cancer diagnosis (75 pairs: 47 during and 28 outside surveillance).
In the whole population, patients with hepatitis B tended to have a poor prognosis than those with hepatitis C (p = 0.160), and this difference became statistically significant among the patients with an advanced hepatocellular carcinoma (p = 0.025). Etiology, Child-Pugh class, gross pathology, and alpha-fetoprotein were the significant independent prognostic factors in the whole population. The distribution of these prognostic factors did not differ between patients with hepatitis B or hepatitis C, both in the whole population and in the subgroup of advanced hepatocellular carcinomas.
Hepatitis B virus-related hepatocellular carcinomas have a greater aggressiveness than hepatitis C virus-related tumors, which becomes clinically manifest once they have reached an advanced stage.
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