Surveillance for hepatocellular carcinoma: A standard of care, not a clinical option

D espite considerable progress in treatment, the overall prognosis of hepatocellular carcinoma (HCC) globally remains grim, because a majority of patients with HCC are identified with an advanced disease that almost invariably prevents the application of potentially curative treatments. Although this accounts for global incidence and mortality rates of HCC to virtually overlap, the only hope for a cure rests on early diagnosis through surveillance with abdominal ultrasound (US) of patients at risk, an endpoint that is achieved in a minority of patients, most clustering in the developed world. This is no surprise, because surveillance involves more than simply a screening test, being framed in a program where tests, recall policies, and quality control procedures are standardized, with significant economic consequences. Although the latter depend on multiple epidemiological and clinical factors, intervals of screening per se add to the never-ending dispute of effectiveness and cost–utility ratio of screening for HCC. Indeed, although the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) share common recommendations for semiannual surveillance with abdominal US in all patients who are at risk for HCC, the Japanese Association of the Liver recommends intensified screening every 3 or 4 months in men with viral cirrhosis or chronic viral hepatitis of increasing age, or in those who have a history of alcohol abuse, because these patients are considered at very high risk for HCC. However, the strategy of intensified screening contrasts with the paradigm that the intervals of screening are not dictated by the level of HCC risk, which may range from 1% to more than 3% per year, but only by the growth rate of the tumor, which takes 6 months to double its volume, on average. Although it is crystal clear that intensified screening seeks to identify liver cancer at the smallest tumor size possible in order to optimize treatment, the effectiveness of this policy is largely questioned. This is also the message of the study by Trinchet et al. in this issue of HEPATOLOGY, where patients with cirrhosis were randomly allocated to standard (6-month) versus intensified (3-month) intervals of screening for HCC. Following patient stratification by site and etiology (most arising from hepatitis C and alcohol), 43 centers in France and Belgium started surveillance with US, with or without serum alpha-fetoprotein determination. Ultimately, the study ended with the randomization of 1278 patients into the two interval arms of US screening only, because the protocol for alpha-fetoprotein was violated in a majority of the patients. This notwithstanding, the good quality of the study was granted by the high rate (88%) of compliance to the EASL guidelines–based protocol, during a median period of 47 months. Interestingly, the two study groups showed similar rates of cumulative 5-year incidence of HCC nodules (10.0% versus 12.3%), cumulative incidence of HCC 30 mm and 20 mm in diameter, access to curative treatments (62% versus 58%), and liver-related mortality (85% versus 86%). However, the fact that the 5-year cumulative incidence of focal lesions was higher in the 3-month arm (41% versus 28%) clearly heralds a greater economic burden to reach a final diagnosis, which might negatively affect morbidity and the cost–utility ratio of intensified screening. Indeed, although the benefits are intuitive, the economic consequences of HCC surveillance strategies are generally poorly appreciated, due to the lack of randomized trials that have evaluated moderators of treatment outcome, such as compliance, heterogeneity of liver disease, and treatment effectiveness, which, in addition to tumor incidence, affect the cost–utility ratio of surveillance. The never-ending argument of cost–utility ratio of surveillance has, in fact, been analyzed by Markov modeling only, and moreover, in the Abbreviations:: AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; US, ultrasound. Address reprint requests to: Massimo Colombo, M.D., 1st Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via F. Sforza 35, 20122 Milan, Italy. E-mail: massimo.colombo@unimi.it; fax: 39-0250320410. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24684 Potential conflict of interest: Dr. Colombo advises, is on the speakers’ bureau of, and received grants from Merck, Bayer, Roche, Bristol-Myers Squibb, and Gilead.