Uncertainty for Screening At-Risk Patients for HCC

Hepatocellular carcinoma (HCC) incidence and mortality continues to increase. The National Cancer Institute projected new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2014 at 33,190 and 23,000, respectively. Current guidelines recommend routine screening for HCC in high-risk patients, including those with hepatitis B or cirrhosis. The rationale for screening is that imaging tests may identify patients with early-stage HCC, and potential options exist for treating patients with early-stage HCC. However, the strength of evidence supporting these guidelines remains controversial, in part because of concerns over the quality and paucity of existing evidence, as well as concerns about the risk for overdiagnosis.

To better understand the incremental benefits and harms of routine HCC screening compared with clinical diagnosis, researchers conducted a systematic review of published literature. The findings showed it remains unclear whether symptomatic screening leads to a survival advantage over a clinical diagnosis [Ann Intern Med. 2014; DOI:10.7326/M14-0558].

For the study, researchers used data from MEDLINE, PsycINFO^®, and ClinicalTrials.gov from inception to April 2014; Cochrane database to June 2013; reference lists; and technical advisors. The study included English-language controlled clinical trials and observational studies that assessed screening versus not screening, studies of harms, and trials comparing different screening intervals. Mortality and adverse events were the primary outcome measures.

The search yielded 1301 citations, and 22 studies met the inclusion criteria. Overall, the researchers
found the strength of evidence on the effects of screening was very low. “Although screening identified patients with early-stage HCC and some of these patients do well with curative therapy, there is very–low-strength evidence from which to draw conclusions about the balance of benefits and harms of screening for HCC,” the researchers noted.

When examining the mortality outcomes of screening, the investigators found that 2 clinical trials and 18 observational studies provided very–low-strength evidence from which to draw conclusions about the mortality effects of HCC screening compared with not screening. Both clinical trials were conducted in China in areas with high HCC prevalence, and most of the patients had hepatitis B with or without
cirrhosis. One cluster, randomized trial included 9757 patients who were offered serum α-fetoprotein testing and ultrasonography every 6 months, and the 9443 participants in the control group were made unaware of the study or actively followed. Death from HCC occurred less frequently in the screening group compared with the control group (83.2 vs 131.5 per 100,000 person-years, respectively; rate ratio, 0.63; 95% confidence interval, 0.41-0.98). The researchers
acknowledged that the study was limited by methodological flaws.

In the second trial, patient-level randomizations stratified by township were used to assign patients with hepatitis B to the screening intervention (n=3712), which consisted of serial α-fetoprotein tests followed by ultrasonography for high α-fetoprotein values, or usual care group (n=1869). Only 28.8% of the screening group participants completed all scheduled testing, but all completed at least 1 screening test. The findings showed that fewer patients had stage 3 HCC in the screening group than the usual care group (19.8% vs 41%, respectively), but HCC mortality was similar in both groups (1138 vs 1114 per 100,000 person-years, respectively), as well all-cause mortality (1843 vs 1788 per 100,000 person-years, respectively). The researchers noted that this trial had an unclear risk of bias because of poor reporting of randomization and allocation concealment techniques.

The group of observational studies compared survival in patients with screen-detected HCC versus those with HCC diagnosed incidentally as part of another work-up or because of symptoms. The results, which included a majority of patients with viral hepatitis or cirrhosis, showed that screening identified patients with earlier-stage disease. However, the researchers pointed out lead- and length-time bias confounded the effects on mortality. Two trials found no survival difference between shorter (3-4 month) and longer (6-12 month) screening intervals.

The researchers found that none of the studies reported direct human harms of screening, and no studies examined the psychological effects of screening. One meta-analysis of 8 studies demonstrated the risk for needle-track seeding from liver biopsy for suspected HCC to be 2.7%.

The researchers acknowledged that a limitation of their review was the exclusion of non-English-
language articles.—Eileen Koutnik-Fotopoulos