Abstract: Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide and the main cause of death in patients with cirrhosis. Secondary prevention of HCC can be accomplished through the serial application of screening tests (ultrasound with or without alpha-fetoprotein) to detect the presence of subclinical lesions amenable to potentially curative treatment, such as surgery and ablation. The efficacy of HCC screening is accepted by hepatologists in terms of decline in cancer-specific mortality, but its translation into clinical practice is less than ideal. The effectiveness of HCC screening is hampered by several factors: failure to identify at-risk patients, failure to access care and failure to detect HCC. For each of these steps, possible improvements are discussed in order to face the changing etiology of cirrhosis and expand the screening of at-risk populations by including selected nonalcoholic fatty liver disease patients.


Keywords: cirrhosis, hepatocellular carcinoma, ultrasound, alpha-fetoprotein, screening


INTRODUCTION

Hepatocellular carcinoma (HCC) represents a leading cause of cancer mortality, being the 5th most common cancer in men and representing the second leading cause of cancer death worldwide.1,2 HCC incidence in the United States and Europe has doubled over the past two decades, and HCC is the main cause of death in patients with cirrhosis.3

Surveillance represents a typical tool for secondary prevention of cancer and entails the serial application of screening tests to detect the presence of HCC among at-risk populations before the neoplasm becomes clinically suspected or evident.

When detected at a symptomatic stage, HCC is almost invariably fatal. By this stage, the cancer is usually large and untreatable, with rapid progression and an interval from diagnosis to death of 3–6 months.4 This pattern characterized the large majority of patients in the era before the development of ultrasound (US) and computed tomography (CT) scan and is still the pattern of presentation where these techniques are either not available or not applied.

However, HCC has a prolonged subclinical growth period5–8 during which curative treatments are often possible. The principal objective of surveillance is, therefore, the detection of subclinical lesions that might be amenable to potentially curative treatment.9–11

Although the efficacy of HCC screening is accepted by hepatologists, its effectiveness, ie, the benefits achieved in real practice and broader populations, is far from ideal. This explains why nonliver scientific societies have not endorsed HCC screening due to the lack of high-quality data. The US Preventive Services Task Force has not adopted an HCC practice guideline, the American Cancer Society makes no recommendation on HCC screening12 and the National Cancer Institute found no evidence that screening decreases mortality from HCC but did find evidence that screening could result in harm.13

Another major issue is the low adherence to screening programs: in order to achieve outcome improvements in HCC, at least 34% of individuals within a cirrhosis population must undergo surveillance to capture an early-stage diagnosis rate of at least 42%.14 In real life, reported HCC surveillance rates in most observational studies in the United States and Europe are far from these values.15–18

The latest meta-analysis, including 22 studies from North and South America, Europe and Asia and 19, 511 patients with advanced fibrosis or compensated cirrhosis (Ishak score ≥3), was published in 2018.19 It revealed an overall adherence rate to HCC surveillance of 52% with wide differences in compliance rates between studies: in fact, it is higher in studies from Europe than in studies from the United States and Asia (70%, 42%, 33%, respectively) and in those patients with cirrhosis compared to patients without (52% and 32%, respectively). However, in the multivariate analysis, the study design (retrospective vs prospective) turned out to be the only independent predictor accounting for differences in adherence levels. Indeed, the true real-life adherence rate was of 39% based on estimates from retrospective studies where selection bias of patients was deemed to be less relevant.

Therefore, there is a need to improve quality data on HCC screening and to recognize the levels at which the screening fails in order to introduce corrections.

HCC SCREENING: CURRENT STATUS

In recent years, guidelines for HCC screening and surveillance have been issued by major liver disease scientific societies in Europe, the United States and Asia.9–11 Such endorsement relies on the assumption that HCC surveillance fulfills all the pre requisites that make the screening policy cost-effective, according to WHO recommendations.

First, HCC is a common cancer that is the 5th most common cancer in the world and is the third cause of cancer-related mortality, as estimated by the WHO (globacan.iarc.fr).

Second, the risk of disease in the target population is great enough to justify the costs (Box 1). Cirrhosis is considered the most important risk factor for the development of HCC, and, therefore, cirrhotics of any etiology are the patients who may benefit most from screening surveillance. Conventionally, the risk of developing HCC refers to the incidence rate of the disease per year in the target population. Several studies of cost-efficacy or cost-utility analysis have been carried out in the last 20 years.20–29 Although these models differed in terms of the inception cohort, input values and assumptions (surveillance techniques and surveillance intervals, the follow-up after identification of HCC, rate of patients undergoing curative treatment and costs), virtually all concluded that surveillance is cost effective and enables a reduction in mortality. All these studies confirmed that the cost efficacy of surveillance is critically dependent on the annual incidence of HCC even though an absolute cut off to institute surveillance was not achieved. Averaging out these studies suggests that surveillance is effective for patients with cirrhosis if the annual incidence of HCC exceeds 1.5–2%. This threshold is currently recommended by the most important international guidelines.9,10

An HCC annual incidence equal to or exceeding 1.5–2% characterizes viral cirrhosis worldwide. A significant risk of cancer, although drastically reduced, still persists for both hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related cirrhosis following viral suppression (HBV) or viral clearance (HCV) by direct-acting antivirals (DAA). For these reasons, both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend maintaining successfully treated patients under surveillance.9,10 

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