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Chen et al. Hepatoma Res 2019;5:12 I http://dx.doi.org/10.20517/2394-5079.2019.03 Page 9 of 17

[20]
[19]
in 2003 , one from Shanghai in 2004 , in which both screened carriers of HBsAg every 6 months. In the
Qidong study, the percentage of cases in stage I were significantly higher in the screening group (29.6%) than
in control group (6.0%), showing short survival benefit from screening, but no difference in 5-year survival
between the groups. The mortality rate in the screened group (1,138 per 100,000 person-years) was not
significantly different from that in the controls (1,114 per 100,000). This trial concluded that screening with
AFP resulted in earlier diagnosis of liver cancer, but the gain in lead time did not result in overall reduction
in mortality in this reported period. In the Shanghai study, the authors reported that the HCC mortality
rate was significantly lower in the screened group (83.2 per 100,000) than in controls (31.5 per 100,000), with
a mortality rate ratio of 0.63 (95%CI: 0.41-0.98). It concluded that the biannual screening with combined
AFP and US in individuals aged 35-59 years reduced HCC mortality after 5-year follow-up. These two trials
have been noticed and/or cited by over a hundred reports or guidelines, irregardless of whether they were in
support or opposition to screening [5,8,21,57,68,103-108] .

Screening recommendation in Western countries
After China’s randomized trials were published, the benefit from screening in people at high risk was
noted by professional societies, such as AASLD [21,105,108] , simply because of the surveillance/screening for
liver cancer had become widely applied, but, there was no evidence of benefit from it worldwide. In these
guidelines on management of HCC, the two randomized trials performed in China mentioned above were
evaluated. The guideline authors were interesting in the result of HCC related mortality that was reduced by
37% throughout the screening for 18,816 individuals with HBV infection in Shanghai, and added positive
comments that these results probably represent the minimum benefit that can be expected from surveillance,
[20]
[19]
because of poor compliance of less than 60% . They also cited the earlier study conducted in Qidong that
failed to show long term survival/mortality-reduction benefit due to patients who were diagnosed with liver
cancer did not undergo appropriate treatment, and suggested that these results should be validated in other
[21]
geographical areas, and that assessing the benefits of surveillance by RCT are still considered necessary .
Since the recommendation was issued, other guidelines or suggestions have been published [106-110] , and
various studies have examined physicians’ knowledge of or adherence to the guidelines and reported
[81]
deficiencies and need for improvement . Most gastroenterologists correctly identified the common high-
risk scenarios, methods, and interval of HCC screening as recommended by AASLD [111] . A recent systematic
review on surveillance detection demonstrated improved survival and increased detection rate of early stage
[68]
HCC . Forty-seven studies from January 1990 through January 2014 with 15,158 patients were identified, of
whom 6,284 (41.4%) had HCC detected by surveillance, being associated with improved early stage detection
(OR: 2.08, 95%CI: 1.80-2.37) and curative treatment rates (OR:2.24, 95%CI:1.99-2.52). HCC surveillance was
associated with significantly prolonged survival (OR: 1.90, 95%CI: 1.67-2.17), even after adjusting for lead-
time bias. It is believed that HCC surveillance is associated with significant improvements in early tumor
[75]
detection, receipt of curative therapy, and overall survival in patients with cirrhosis , and may also reduce
the mortality of HCC [20,74] .

Debates on screening effectiveness
Although the effectiveness of liver cancer screening has been recognized in the literature and is also included
in the AASLD surveillance guidelines for liver cancer [55,21] , there have been different opinions and even
opposition to the choice of at-risk populations, the necessity, and the effectiveness of screening. Lederle and
Pocha [112] were opposed to the existing screening programs by criticizing the 2005 AASLD recommendations
[21]
for HCC screening , arguing that the recommendations were based upon trials from China [19,20] , which
failed to account for clustering in the analysis (a cluster randomized trial cannot be analyzed at the patient
level), hence they state “Ignoring the clustering results in confidence intervals which are too narrow and P
values which are too small; hence it is likely to produce spuriously significant differences” [57,113] . Furthermore,
they questioned the evidence obtained from the study that is not a level I evidence to support the liver
cancer screening, and is not necessarily applicable to Western populations because it was conducted in a
hepatitis B population in China, and most HCC in West countries and North America is caused by hepatitis