Screening for Liver Cancer: Another Piece of the Puzzle? See Article on Page 1840
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espite the fact that most hepatologists accept the need for screening for hepatocellular carcinoma (HCC), it remains a controversial 1,2 issue. As with cancer screening for so many other tumors, proving that HCC screening is effective has been difficult. Ideally, a cancer screening program, to be effective, should result in a decrease in diseasespecific mortality (i.e., fewer people should die of cancer). This can only be demonstrated with certainty in a prospective, randomized, controlled trial (RCT) in which one group is screened and the other not screened, with mortality as an outcome. For HCC, there are two such trials, both conducted in China.3,4 The first failed to show a mortality difference. However, this study used only alpha-fetoprotein (AFP) as the screening test. Subsequent knowledge has clearly shown that AFP is an inadequate screening test. Furthermore, the study report did not indicate what treatments were applied to patients in whom HCC was detected; but in the era when this study was conducted, China was a poor country, with the costs of surgery being borne by the patient. This likely led to treatment not being applied to all those who might have benefited. The second study did show a substantial reduction in mortality, but this study has been criticized on the basis that the analysis was statistically incorrect. This criticism does decrease confidence in the results of this study, but does not say that screening is ineffective. There is considerable evidence, albeit of lower quality, that supports that screening is likely to reduce HCC mortality. This uncertainty has implications for public policy. Payers want certainty. To date, with the exception of Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; RCT, randomized, controlled trial; US, ultrasound. Address reprint requests to: Morris Sherman, M.B., B.Ch., Ph.D., F.R.C.P(C)., University of Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail: morris.sherman@ uhn.on.ca; fax: 416-591-2107. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26936 Potential conflict of interest: Nothing to report.
Japan and South Korea, no governmental agency has recommended HCC screening. Should payers wait for randomized, controlled data, the only data that bring certainty, before recommending and paying for HCC screening? For many reasons, although desirable, initiation of an RCT of HCC screening is unlikely, and if initiated, completion is also unlikely. Because there is at least suggestive evidence of a substantial benefit to HCC screening, payers and government agencies have to consider the issue and make their decisions based on available evidence. What evidence, short of RCT data, might be sufficient to convince payers and government agencies that HCC screening should be recommended? Case-control studies showing earlier diagnosis (stage migration) are not proof of efficacy nor are retrospective studies, many of which are subject to lead-time bias. Prospective, nonrandomized studies with mortality as an endpoint are better than retrospective studies, but are all subject to bias. This bias can be, to some extent, mitigated by using propensity score matching (i.e., matching study subject and control on criteria that are important to the risk of developing HCC). This principle has been well demonstrated in a study of the efficacy of entecavir in reducing HCC incidence.5 In this issue of HEPATOLOGY, a group from Taiwan report on a study in which a risk score is applied to identify a cohort of subjects who are deemed, by virtue of having an elevated risk score, to be at higher risk of HCC.6 HCC screening with a one-time ultrasound (US) was offered. The comparison groups were a simultaneous cohort being the other inhabitants of the same counties who were not invited to participate, as well as a historical control group. The study showed that those who underwent screening, albeit one time, had a lower HCC mortality than those who did not, despite the fact that the screened group was at higher risk for HCC and therefore at higher risk of HCCrelated death. Several aspects of this study merit comment. The Taiwan study selected patients on the basis of two risk scores: one for patients with viral hepatitis and one for those free of viral hepatitis. The viral hepatitis risk score included AFP, alanine aminotransferase, and platelet count
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espite the fact that most hepatologists accept the need for screening for hepatocellular carcinoma (HCC), it remains a controversial 1,2 issue. As with cancer screening for so many other tumors, proving that HCC screening is effective has been difficult. Ideally, a cancer screening program, to be effective, should result in a decrease in diseasespecific mortality (i.e., fewer people should die of cancer). This can only be demonstrated with certainty in a prospective, randomized, controlled trial (RCT) in which one group is screened and the other not screened, with mortality as an outcome. For HCC, there are two such trials, both conducted in China.3,4 The first failed to show a mortality difference. However, this study used only alpha-fetoprotein (AFP) as the screening test. Subsequent knowledge has clearly shown that AFP is an inadequate screening test. Furthermore, the study report did not indicate what treatments were applied to patients in whom HCC was detected; but in the era when this study was conducted, China was a poor country, with the costs of surgery being borne by the patient. This likely led to treatment not being applied to all those who might have benefited. The second study did show a substantial reduction in mortality, but this study has been criticized on the basis that the analysis was statistically incorrect. This criticism does decrease confidence in the results of this study, but does not say that screening is ineffective. There is considerable evidence, albeit of lower quality, that supports that screening is likely to reduce HCC mortality. This uncertainty has implications for public policy. Payers want certainty. To date, with the exception of Abbreviations: AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; RCT, randomized, controlled trial; US, ultrasound. Address reprint requests to: Morris Sherman, M.B., B.Ch., Ph.D., F.R.C.P(C)., University of Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail: morris.sherman@ uhn.on.ca; fax: 416-591-2107. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26936 Potential conflict of interest: Nothing to report.
Japan and South Korea, no governmental agency has recommended HCC screening. Should payers wait for randomized, controlled data, the only data that bring certainty, before recommending and paying for HCC screening? For many reasons, although desirable, initiation of an RCT of HCC screening is unlikely, and if initiated, completion is also unlikely. Because there is at least suggestive evidence of a substantial benefit to HCC screening, payers and government agencies have to consider the issue and make their decisions based on available evidence. What evidence, short of RCT data, might be sufficient to convince payers and government agencies that HCC screening should be recommended? Case-control studies showing earlier diagnosis (stage migration) are not proof of efficacy nor are retrospective studies, many of which are subject to lead-time bias. Prospective, nonrandomized studies with mortality as an endpoint are better than retrospective studies, but are all subject to bias. This bias can be, to some extent, mitigated by using propensity score matching (i.e., matching study subject and control on criteria that are important to the risk of developing HCC). This principle has been well demonstrated in a study of the efficacy of entecavir in reducing HCC incidence.5 In this issue of HEPATOLOGY, a group from Taiwan report on a study in which a risk score is applied to identify a cohort of subjects who are deemed, by virtue of having an elevated risk score, to be at higher risk of HCC.6 HCC screening with a one-time ultrasound (US) was offered. The comparison groups were a simultaneous cohort being the other inhabitants of the same counties who were not invited to participate, as well as a historical control group. The study showed that those who underwent screening, albeit one time, had a lower HCC mortality than those who did not, despite the fact that the screened group was at higher risk for HCC and therefore at higher risk of HCCrelated death. Several aspects of this study merit comment. The Taiwan study selected patients on the basis of two risk scores: one for patients with viral hepatitis and one for those free of viral hepatitis. The viral hepatitis risk score included AFP, alanine aminotransferase, and platelet count
