Does Screening for Hepatocellular Carcinoma Improve Outcomes in Patients with Cirrhosis?

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Despite widespread recommendations to screen patients with cirrhosis for hepatocellular carcinoma (HCC), a recent study (AM Moon et al. Gastroenterol 2018; 16: 1777-85) found “No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients with Cirrhosis.” The title of the study did not make sense to me based on previous publications that have noted increased risk of HCC in patients with cirrhosis and the presumption that screening would allow effective interventions to prevent death due to HCC.  So I looked at the study a little closer:

Background/Methods: The authors utilized a matched case-control study within the U.S. Veterans Affairs health care system to determine whether ultrasonography (US) or alpha-fetoprotein (AFP) screening was associated with decreased cancer-related mortality.

They identified 238 patients with cirrhosis who died of HCC between 2013-2015 –all of whom had a diagnosis of cirrhosis at least 4 years before the diagnosis of HCC.  Then, they matched them with a control patient with cirrhosis who did not have HCC and had been identified at least 4 years prior to matched case’s HCC.

Key findings:

  • There was no significant difference between the cases and the controls in the proportions who underwent screening:
  • For U/S screening: 52.9% cases and 54.2% for controls.
  • For AFP (serum) screening, 74.8% vs 73.5% respectively.
  • For either U/S or AFP screening, 81.1% vs 79.4%.
  • For both U/S and AFP screening, 46.6% vs 48.3% respectively.
  • Table 4 provides odds ratios and adjusted odds ratios for the cases compared to controls.  The Adjusted Odds ratios for U/S 0-4 years before index case was 0.95, for AFP 1.08, and for either U/S or AFP 1.11.

The authors found that HCC screening with U/S and/or AFP was not associated with decreased risk of HCC-related mortality.

In their study, the authors note that most studies on HCC screening have been observational which have numerous limitations including lead-time biases (which can overestimate the benefits of screening) and patient selection.  Two randomized controlled trials reached conflicting conclusions; these trials were conducted in China where HCC is mainly associated with hepatitis B infection.

The authors point out that liver societies like AASLD and EASL have recommended U/S every 6 months with or without AFP measurements for HCC surveillance in patients with cirrhosis.  However, non-liver societies have NOT “endorsed HCC screening because of the lack of high-quality data.”  Neither the US Preventive Services Task Force nor the American Cancer Society make recommendations for HCC screening.  And, “the National Cancer Institute found no evidence that screening decreases mortality from HCC but did find evidence that screening could result in harm.”

Strengths of this study:

  • All VA patients have access to medical care; this limits bias due to access to HCC screening
  • The matched-case control design with random controls across a system that delivers care to 8 million veterans across the country indicates that the findings are likely  “typical of community-based settings” and likely to yield “estimates of the impact of screening …[that] approximates the results that would be expected from a randomized controlled trial”

Why Have Previous Studies Indicated that HCC Screening is Worthwhile?

  • According to the authors, even though HCC detected by screening is on average detected at an earlier stage than those detected due to symptoms, “this does not prove that screening leads to earlier detection. Another explanation is that screening is more likely to identify slow-growing tumors, which have a lower stage, and more likely to miss the fast-growing tumors, which are identified at a higher stage by symptoms.”
  • “It is possible that the HCCs most likely to lead to death are the HCCs least likely to be identified by current screening modalities at an early stage.”
  • In addition,  “whether early treatment for HCC in patients with cirrhosis leads to a decrease in case fatality is questionable.”  Patients who receive surgical resection or locoregional treatments remain at risk for recurrent HCC, new HCC and progressive liver dysfunction.  While liver transplantation can cure HCC and cirrhosis, only a “small minority of patients with HCC undergo liver transplantation.”  In 2012, only 1,733 patients received liver transplantation for HCC out of a reported 24,696 incident cases.

My take: This study offers a lot of insight regarding HCC screening and questions its usefulness, though I doubt this study will change how most hepatologists practice.

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