The other randomized control trial took place in Toronto, and included 1069 patients, 71% of whom were of Asian ancestry. Subjects had AFP testing every 6 months, and half were randomly assigned to have US performed every 6 months.5 Eight of the 11 incident tumors would have been diagnosed based on AFP levels alone, and 3 would have been missed with US alone. The authors conclude that for AFP, sensitivity=64.3% and specificity=91.4%; for US, sensitivity=78.8% and specificity=93.8%. However, their study was too small to determine if AFP/US is superior to AFP for hepatocellular carcinoma screening in a HBsAg+ population. They estimate that detecting such a difference would take a sample size of 10,000 or more.
Both studies have important flaws. Neither study applied a reference standard test (such as a computed tomography scan or magnetic resonance imaging) to both study arms. Carcinomas may have been undetected by either AFP or US. Without knowing the real prevalence of hepatocellular carcinoma, the true sensitivity and specificity for AFP, US, and AFP/US in these studies cannot be determined. Both studies included prevalent tumors (tumors diagnosed during the very first screening cycle) in their analysis. Approximately 20% of detected carcinomas in both studies were present at the start of the studies and did not represent newly incident tumors detected by regular screening.3,5
Both of these trials would be improved if they started with cohorts known to be disease-free at baseline. Additionally, the Shanghai study randomized patients in clusters. The only English-language report of this study did not describe whether adjustments for this were made in analysis;5 failing to do so could overestimate the benefit of screening.
Recommendations from others
The American Association for the Study of Liver Disease recommends that carriers of the hepatitis B virus who are at high risk for developing hepatocellular carcinoma—men aged >45 years, those with cirrhosis or a family history of hepatocellular carcinoma—should be screened periodically with AFP/US. Also consider periodic screening for low-risk HBsAg+ patients who are from an area where hepatocellular carcinoma is endemic (SOR: C, based on expert opinion or descriptive epidemiology).6