Reply
Authors: Morris Sherman, Jordi Bruix
Journal: Hepatology (2011)

We thank Drs. Marrero and El-Serag1 for their comments on the recently published guidelines on the management of hepatocellular carcinoma (HCC).2 The use of alpha-fetoprotein (AFP) as a screening test for HCC has long been controversial, although it should not be so. The evidence is clear that AFP is a poor screening test. In response to Drs. Marrero and El-Serag,1 we offer the following comments: We agree that a randomized controlled trial is the best evidence of the efficacy of screening, and the only such trial is that published from China in 2004.3 The study compared screening with AFP and ultrasound (US) to no screening and demonstrated a 37% decrease in mortality in the screened group. This outcome could have been due to AFP alone, to ultrasonography alone, or to both. Drs. Marrero and El Serag have assumed that both AFP and US are necessary. However, a separate analysis of data from the same study indicated that adding AFP to US did increase the detection rate slightly, but also increased the false-positive rate and more than doubled the cost per tumor found compared to US alone.4 Other support comes from cost efficacy analyses. Of the several that have been published so far, the one that most closely mimics our current approach to HCC is that of Andersson et al.,5 which shows that screening with US is cost-effective, but when AFP is added there is little benefit and considerable increased cost. A separate analysis6 suggested that the most cost-effective method of screening was with AFP alone, but adding US increased efficacy although it also increased cost. Some of the assumptions about the sensitivity and specificity of AFP in this analysis was suspect, so the AFP analysis must be taken with a grain of salt. Thus, these studies would lead one to conclude that adding AFP to US does not add much. Furthermore, there are many studies that have examined the efficacy of AFP as a diagnostic test,7-10 but few that have evaluated AFP as a screening test.11, 12 Results from these studies are completely discordant, with one showing that AFP as the sole screening test is effective in identifying treatable cancers12 and the other suggesting the opposite.11 In general, as expected, those studies in which AFP is used as a diagnostic test show a better performance. For example, Trevisani et al.7 showed that as a diagnostic test, the positive predictive value of AFP in a population where 50% of the cases had HCC, and at a cutoff of 20 ng/mL, was 85%. However, if the prevalence of HCC was reduced to 5% (still much too high for a screening population), the PPV was only 25%. Even if the cutoff was raised to 400 ng/mL, the PPV was only 60% at HCC prevalence of 5%. Dr. Marrero undertook a similar study recently,8 and demonstrated that the sensitivity of AFP at a cutoff of about 11 ng/mL overall was only 66%. In early stage disease (defined essentially as the Milan transplant criteria, or BCLC stage A), the sensitivity was only 53% at an AFP cutoff of 20 ng/mL. It is a question of whether the glass is half full or half empty. To Dr. Marrero and his colleagues, this is adequately sensitive as a screening test, but to us, it is not. We do not believe that identification of lesions of 5 cm or multiple lesions should be the target size for a screen-detected lesion. The cure rate (apart from transplantation) is less than optimal for this size of lesion. A 5-cm tumor falls within criteria for transplantation, which has a high cure rate, but the proportion of all patients with HCC who get a transplant is very small,13 and is unlikely to have any effect on overall mortality. (Reduction in mortality is ultimately the goal of screening, and tests that do not reduce mortality in the screened population are useless). AFP is not sensitive enough to identify the majority of these small HCCs. US, in contrast, does have adequate sensitivity, at least in Europe, Japan, and Canada, where the majority of HCCs identified in patients undergoing screening are smaller than 3 cm. Even in the United States, a meta-analysis in which Dr. Marrero participated showed that US was more sensitive than AFP, the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) study results notwithstanding.14 There seem to be two reasons why AFP testing remains popular. One is an inadequate appreciation of the appropriate target lesion size as discussed above, and the second, we think, is that AFP is a marker of increased HCC risk. Therefore, it is not surprising that HCC is found more often in patients with an elevated AFP than in those with normal AFP. However, this does not make AFP a good screening test. The false-positive rate of AFP testing is high, but there is little data on the costs and harms of investigating these false-positives. Furthermore, there is ample evidence that AFP is a marker of poor prognosis. Screening should identify good prognosis lesions. Finding poor prognosis lesions is unlikely to improve overall survival. Drs. Marrero and El Serag imply that effectiveness (as opposed to efficacy) of screening may be reduced because of the need for regular US that might reduce the frequency of screening. This is a theoretical concern, but the alternative would be not to perform US and only to use AFP. There is no data to support this practice. No guideline suggests using only AFP. Given all the negative data, to recommend that AFP be used as the single screening test is, in our view, unsupportable. Thus, although the randomized controlled study of HCC screening used both AFP and US, we believe that contribution of AFP to the outcome was minimal, and maintain our position that it should not be used. US is a better test, and we should not be recommending inferior tests in guidelines such as this. Morris Sherman M.D.*, Jordi Bruix M.D. , * Toronto General Hospital, Toronto, Canada, Liver Unit, BCLC Hospital Clínic, Barcelona, Spain.