A Systematic Review: Screening for Hepatocellular Cancer in Chronic Liver Disease

In the VA healthcare system, there has been a marked increase in the prevalence of cirrhosis from chronic hepatitis C infection with a corresponding increase in the number of hepatocellular cancer (HCC) diagnoses. From 1996 to 2006, the prevalence of cirrhosis among Veterans with chronic hepatitis C infection rose from 9% to 18.5%, and the prevalence of HCC rose from 0.07% to 1.3%. While, on average, the five-year survival of HCC is low (13% to 16.5%), the survival of early-stage disease has risen. Several professional guidelines recommend HCC screening, mainly in patients with chronic hepatitis B or liver cirrhosis; however, screening remains controversial, in part, because of concerns over the quality and paucity of existing evidence, and because there have been concerns raised about over-diagnosis and patient harms in other cancer screening programs.

The VA Evidence-Based Synthesis Program located in Portland, OR conducted a systematic review of the published literature to examine:

1. Mortality effects of routine HCC screening in patients with chronic liver disease compared to clinical or incidental diagnosis;
2. Harms of routine HCC screening in patients with chronic liver disease; and
3. Mortality effects and harms of treating screen-detected, or early-stage HCC.

Investigators reviewed the literature from database inception to March 2013. After applying inclusion/exclusion criteria, 35 studies and two systematic reviews of treatment modalities were used to provide the Summary, which is followed by more detailed information.

Summary:
There is very low strength evidence from which to draw conclusions about the effects of HCC screening on mortality in high-risk patients with chronic liver disease. Screening tests can identify early stage HCC, and patients who are selected for surgical treatment often have good long-term survival, but some treatments may be associated with substantial harms. Therefore, trials examining the balance of benefits and harms of HCC screening in patients with chronic liver disease should be considered.

Results:
Effects of Screening on Mortality: RCTs
Two trials, both conducted in China, compared the effects of screening to no screening on mortality among patients, mainly with hepatitis B. One trial used a cluster-randomized design to assign individuals from factories, businesses, and schools to screening or no screening groups. Screening group participants (n = 9,757) were offered serum AFP (alpha-fetoprotein) testing and ultrasonography every six months. The primary outcome of HCC mortality occurred less frequently in the screening group (83.2/100,000 person-years versus 131.5/100,000 person-years). However, this trial carried a high risk of bias because of several serious methodological limitations that threaten the validity of the results.

The second trial used patient-level randomization by township to assign hepatitis B patients to the screening intervention (n = 3,712), which consisted of serial AFP tests followed by ultrasound for high AFP values, or the usual care group (n = 1,869). HCC mortality was similar in both groups (1,138/100,000 person-years versus 1114/100,000 person-years), as was all-cause mortality (1,843/100,000 person-years versus 1,788/100,000 person-years). This trial carried an unclear risk of bias because of poor reporting of randomization and allocation concealment techniques.

Two additional trials – one with unclear risk of bias and the other with low risk of bias – found that patients screened with ultrasound at shorter intervals (3 and 4 months) had similar survival as patients screened at longer intervals (6 and 12 months).

Effects of Screening on Mortality: Observational Studies
Sixteen observational studies showed that screening detects patients with earlier stage disease, more of whom undergo potentially curative therapy. Median survival ranged among studies from 12 to 56 months in the screening group, and from 3 to 37 months in the non-screening group. Three-year survival ranged from 22% to 67% in the screening group, and from 15% to 51% in the non-screening group. However, it is impossible to say whether the longer survival in screen-detected patients is a true effect of screening or, rather, reflects lead- and length-time biases inherent to all observational studies, and selection biases which were common in many of the studies.

Harms of Screening
None of the included studies reported direct harms of screening, but the physical harms of HCC screening using ultrasound and/or AFP – which were the most commonly studied screening modalities – are likely to be minimal. However, most patients with positive screening ultrasound and/or AFP undergo further confirmatory testing. In most of the studies, confirmatory testing was done with CT and, less commonly, with MRI or liver biopsy, though very few studies reported rates of actual testing used for diagnosis. One study found that contrast-enhanced CT was associated with adverse events in 13% to15% of patients, while another found mild-moderate adverse events in 25% of patients receiving gadoxetic acid-enhanced MRI. No studies evaluated the psychological harms of screening.

Effects of Treating Screen-Detected HCC
No studies specifically enrolled patients with screen-detected HCC, so investigators examined studies of patients with early-stage HCC as a way of approximating screen-detected disease. Overall, there is little evidence from which to draw conclusions about the net benefits of actively treating early-stage HCC compared to conservative treatment. Observational studies show that patients selected for treatment with OLT (orthotopic liver transplant), resection, or RFA (radiofrequency ablation) had good long-term survival (27% to 75%) that was substantially higher than in patients not selected for such therapy (0% to 30%), but it is unclear whether this reflects a true effect of treatment or confounding by indication. Serious harms occurred in 1.8% to 20% of patients, depending on the intervention.

Future Research:
Research to more definitively evaluate the balance of benefits and harms of treating early-stage HCC is imperative. Even in the absence of randomized controlled trials of screening, observational studies using well-designed registries of HCC patients, their treatments, complication rates, and long-term outcomes could prove useful. These registries should include consecutive patients and prospectively collect clinical information about potential adverse effects over time. Studies examining the psychological impact of screening also are needed. In addition, current imaging tests can identify small, early-stage HCCs. Thus, future studies should evaluate the contemporary natural history of such lesions, and consideration should be given to treatment trials that include a watchful-waiting arm for very early HCC.

A Cyberseminar session on this ESP Report is scheduled for Wednesday, July 23, 2014 from 3:00pm to 4:00pm (ET). To register, go to the HSR&D Cyberseminar web page.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers — and to disseminate these reports throughout VA.

Reference

Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R, Quinones A, Motu'apuaka M, Jou JH. Screening for hepatocellular cancer in chronic liver disease: a systematic review. VA-ESP Project #05-225; 2013.

View the full report (**VA Intranet only**):
http://vaww.hsrd.research.va.gov/publications/esp/hepatocellular.cfm

Please feel free to forward this information to others!

Read past HSR&D Management e-Briefs on the HSR&D website.

This Management eBrief is a product of the HSR&D Evidence Synthesis Program (ESP). ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of the HSR&D Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

See all reports online.