Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis.

BACKGROUND & AIMS: Sorafenib and transarterial (90) Y-radioembolization (TARE) are possible treatments for Barcelona Clinic Liver Cancer (BCLC) intermediate-advanced stage hepatocellular carcinoma (HCC). No study directly comparing sorafenib and TARE is currently available. This single-centre retrospective study compares the outcomes achieved with sorafenib and TARE in HCC patients potentially amenable to either therapy. METHODS: Seventy-four sorafenib (71 ± 10 years, male 87%, BCLC B/C 53%/47%) and 63 TARE HCC patients (66 ± 9 years, male 79%, BCLC B/C 41%/59%) were included based on the following criteria: Child-Pugh class A/B, performance status ≤1, HCC unfit for other effective therapies, no metastases and no previous systemic chemotherapy. RESULTS: Median overall survivals of the two groups were comparable, being 14.4 months (95% CI: 4.3-24.5) in sorafenib and 13.2 months (95% CI: 6.1-20.2) in TARE patients, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. Two TARE patients underwent liver transplantation after successful down-staging. To minimize the impact of confounding factors on survival analysis, propensity model matched 32 patients of each group for median age, tumour gross pathology and the independent prognostic factors (portal vein thrombosis, performance status, Model for End Liver Disease). Even after matching, the median survival did not differ between sorafenib (13.1 months; 95% CI: 1.2-25.9) and TARE patients (11.2 months; 95% CI: 6.7-15.7), with comparable 1-, 2- and 3-year survival rates. CONCLUSIONS: In cirrhotic patients with intermediate-advanced or not-otherwise-treatable HCC, sorafenib and TARE provide similar survivals. Down-staging allowing liver transplantation only occurred after TARE.

Estimation of lead-time bias and its impact on the outcome of surveillance for the early diagnosis of hepatocellular carcinoma.

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.

QT interval prolongation by acute gastrointestinal bleeding in patients with cirrhosis.

BACKGROUND & AIMS: QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning. METHODS: We reviewed the clinical records of 70 consecutive cirrhotic and 40 non-cirrhotic patients with acute gastrointestinal bleeding. All patients had been evaluated before bleeding (T0) and were re-evaluated at the time of bleeding (T1) and 6 weeks afterwards (T2). RESULTS: QT corrected by heart rate (QTc) lengthened at T1, returning towards baseline values at T2 (mean ± SEM; from 415.9 ± 4.3 to 453.4 ± 4.3 to 422.2 ± 5.7 ms, P < 0.001) in cirrhotics; contrariwise, QTc did not change in non-cirrhotic patients. The 6-week mortality was 29.6% among cirrhotic patients, while no control patient died. At T1, patients who died had longer QTc (P = 0.001) and higher model of end-stage liver disease (MELD) score (P < 0.001) than survivors. MELD and QTc independently predicted survival. Their areas under the ROC curve were 0.88 (CI 95% 0.78-0.95) and 0.75 (CI 95% 0.63-0.85) respectively; the best cut-off values were MELD ≥20 and QTc ≥ 460 ms. Based on these factors, the 6-week mortality was: 0% for patients without risk factors, 32.1% for those with one risk factor and 70.6% for those with both (P < 0.001). CONCLUSIONS: Acute gastrointestinal bleeding further prolongs QTc in cirrhosis. This abnormality independently predicts bleeding-induced mortality. The combined measurement of QTc interval and MELD can clearly identify three patient strata at increasing risk of bleeding-related mortality, thus improving the decision-making for these patients.

Cost-effectiveness of liver cancer screening.

Screening for primary liver cancer means surveillance for hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. Detection of HCC for curative treatment is increased by surveillance, but target population, optimal periodicity and cost-effectiveness aspects are still debated issues. The aim of surveillance is to obtain a reduction in HCC-related mortality and this is usually achieved through an early diagnosis that increases both applicability and cost-effectiveness of curative treatments. The aim of the present review is to analyse economic aspects of HCC surveillance. Articles that assessed cost-effectiveness of surveillance for HCC, published between 1996 and February 2013, were reviewed in order to verify the cost-effectiveness of surveillance, its optimal periodicity, the target population and the role of alternative surveillance strategies. International guidelines are currently based on the results of such cost-effectiveness analyses, highlighting the importance of the release of cost-effectiveness-guided guidelines for HCC management.

Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it?

Surveillance for hepatocellular carcinoma (HCC) is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy. Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments. Repetition of liver ultrasonography (US) every 6 mo is the recommended surveillance program to detect early HCCs, and a positive US has to entrain a well-defined recall policy based on contrast-enhanced, dynamic radiological imaging or biopsy for the diagnosis of HCC. Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance, the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure. Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC. The promotion of specific educational programs for practitioners, clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.

Outcome of hepatocellular carcinoma in human immunodeficiency virus-infected patients.

BACKGROUND: Although the number of human immunodeficiency virus-infected patients with chronic liver disease is increasing, the impact of human immunodeficiency virus on hepatocellular carcinoma outcome remains unclear. AIMS: This single centre study investigated whether human immunodeficiency virus infection per se affects the hepatocellular carcinoma prognosis. METHODS: Forty-eight human immunodeficiency virus-infected and 234 uninfected patients consecutively diagnosed with hepatitis virus-related hepatocellular carcinoma from January 2000 to December 2009 were retrospectively enrolled. Hepatocellular carcinoma was staged according to Cancer of the Liver Italian Program criteria. Survival and independent prognostic predictors were evaluated. Survivals were also compared after adjustment and matching by propensity score. RESULTS: Compared to human immunodeficiency virus-uninfected subjects, infected patients were more likely to be males, were younger, had fewer comorbidities and the tumour was more often detected during surveillance. Liver function, tumour characteristics and treatments did not significantly differ between the two groups. Nevertheless, median survival of human immunodeficiency virus-infected patients was approximately half that of their counterpart (16 months [95% confidence interval: 7-25] vs. 30 months [95% confidence interval: 25-35]; p=0.0354). Human immunodeficiency virus infection, Cancer of the Liver Italian Program score and hepatocellular carcinoma treatment were independently associated with mortality. Notably, human immunodeficiency virus infection doubled the risk of dying. These results were confirmed by propensity analysis. CONCLUSION: Human immunodeficiency virus infection per se worsens the prognosis of patients with virus-related hepatocellular carcinoma.

Effectiveness of α-fetoprotein for hepatocellular carcinoma surveillance: the return of the living-dead?

The evaluated article assesses the effectiveness in clinical practice of surveillance with ultrasound (US) and α-fetoprotein (AFP) in patients at risk of developing hepatocellular carcinoma. After a median follow-up of 3.5 years, among the 442 enrolled patients with cirrhosis, 41 developed tumor (annual incidence, 2.8%). Twenty-three hepatocellular carcinomas were diagnosed at Barcelona Clinic Liver Cancer early stage (single tumor <5 cm or ≤3 tumors each <3 cm). Two hundred and seventy one patients (61.3%) underwent 'consistent' (US done at least annually) surveillance, whereas 107 (24.2%) and 64 (14.5%) patients underwent 'inconsistent' and 'no surveillance', respectively. The per-patient sensitivity was 43.9% for US (58.1% excluding cases where US was inconsistently performed) and 65.9% for AFP >20 ng/ml. Specificity was 91.5% for US and 90.5% for AFP. The combination of the tests increased the sensitivity to 90.2%, with a small decrease in specificity (83.3%). In a real-world setting, the combination of US and AFP would be the most effective for hepatocellular carcinoma surveillance.

What is the probability of being too old for salvage transplantation after hepatocellular carcinoma resection?

BACKGROUND: The strategy of salvage transplantation for patients with hepatocellular carcinoma is based on the premise that tumour recurrence will be still transplantable at the time of recurrence. However, patients can not only present non-transplantable recurrence but can also be over the age limit accepted for transplantation. AIMS: To measure the risk of being too old for salvage transplantation of patients resected for hepatocellular carcinoma within Milan criteria. METHODS: A Markov simulation model was developed on the basis of published literature. RESULTS: The risk of being too old for salvage transplantation depends on the time-span between age at hepatic resection and age limit, and the expected median waiting-time. Patients resected at an age 2 or 3 years below the age limit carry a risk of being too old that overcomes the probability of receiving transplantation. Salvage strategy can cause harm that depends on the tumour characteristics and degree of portal hypertension, becoming maximal for patients with multiple tumours, clinical signs of portal hypertension and increased bilirubin levels. CONCLUSIONS: The best strategy to adopt should be balanced between the risk of being too old and the expected transplant benefit, but salvage strategy could be pursued if it did not turn into significant harm in comparison to primary transplantation.