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Chen et al. Hepatoma Res 2018;4:72 I http://dx.doi.org/10.20517/2394-5079.2018.103 Page 3 of 16

MEDLINE search Cochrane Library
(n = 4,557) (n = 273)

Records after duplicates removed
(n = 4,571)

Irrelevant studies based on
title and study aims excluded
(n = 4,457)

Abstracts reviewed
(n = 114)
Full-text articles not
available
(n = 41)

Full-text articles
assessed for eligibility
(n = 73)

Excluded per exclusion
criteria (sample size of less
than 100 in either arm)
(n = 44)

Studies included in
qualitative synthesis
(n = 29)

Figure 1. Study selection flowsheet [64]

randomized controlled trials and cohort studies with more than 100 subjects in the surveillance and non-
[12]
surveillance groups were included for qualitative analysis [Figure 1] .

Randomised trials
To date, there were only two randomised trials, both done in China, directly comparing patients with sur-
veillance to no surveillance. In both trials, the study population was exclusively patients with chronic hepa-
titis B infection (positive serum hepatitis B surface antigen). The first study by Chen et al in 2003 conducted
surveillance with six-monthly serum alpha-fetoprotein (AFP), followed by ultrasound for patients with high
[12]
[11]
AFP levels . No difference in mortality was found in the two groups. Zhang et al. subsequently con-
ducted surveillance with AFP with US 6-monthly in two randomized groups of hepatitis B patients, and a
significant mortality difference was found with a mortality rate ratio of 0.63 (95% CI: 0.41-0.98). These two
trials were heavily criticized due to the poor compliance rate in surveillance group, as well as the limited in-
formation on study design and a high risk of bias [Table 1].

Other randomized controlled trials (RCT) done in Europe and Taiwan addressed the impact of ultrasound
[13]
surveillance intervals. Trinchet et al. conducted a multicenter RCT comparing 3-monthly to 6-monthly
ultrasound surveillance on HCC patients in France and Belgium. Study population was histology-proven
cirrhosis and the main etiologies were alcohol and viral hepatitis. Three-monthly ultrasound detects more