One could argue that a single RCT is less than ample evidence to base conclusions, but this narrowed approach fails to capture the greater depth of information that supported the recommendation. A class II recommendation would indicate conflicting evidence and/or a divergence of opinion about the usefulness

and efficacy of a particular diagnostic evaluation. This would be an unfair “downgrading” of the evidence and expert opinion available to us at this time. In addition to the Chinese RCT, there are less-strong lines of evidence that also suggest that screening HSP inhibitor drugs for HCC is effective in reducing mortality. These include cost-efficacy analyses in populations with hepatitis C and cirrhosis showing that screening is effective in reducing mortality and can do so at an acceptable cost,13-21 and many studies that show stage migration (i.e., diagnosis at an earlier stage of disease) with screening.22-26 Stage migration is not, of itself, evidence of the efficacy of screening. However, it is a necessary condition for screening to be effective. If

earlier diagnosis cannot be achieved, screening will not be of benefit. Many studies of screening are subject to lead-time bias. However, there are some studies that correct for lead-time bias,27, 28 and these show that screening prolongs survival. Although efficacy of screening is determined Crizotinib clinical trial by a decrease in mortality, and not by improved survival, improved survival is a necessary accompaniment of decreased mortality. Although the Chinese

RCT can be criticized, it is the largest study of its either kind, and it does confirm many other studies that support that screening is likely to decrease mortality from HCC. This was the basis for the recommendation in the AASLD guidelines. One of the challenges in HCC screening is determining when the risk is high enough to warrant screening. The guidelines were careful to indicate what the basis was for making the recommendations about who was at sufficient risk to warrant screening and how that assessment was reached, allowing readers to assess for themselves the strength of the evidence. The investigators of the Annals of Internal Medicine article express the concern that the “rush to judgment” will make it more difficult to undertake an RCT in North America. This may be so, but this is by no means the only factor making such a trial very difficult to conduct. Previous attempts to establish an RCT of liver cancer screening have failed. Sample-size calculations suggest that the study will require upward of 10,000 subjects. If the population is to be stratified for baseline factors, such as age, underlying liver disease, stage of liver disease, hepatitis B viral load, and so on, the sample size will be even larger.