Serological Surveillance for hepatocellular carcinoma: Time to quit

COMMENTARY ON: Des-gamma-carboxy Prothrombin and Alpha fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim HY, Lee WM, Bonkovsky HL, Dienstag JL; HALT-C Trial Group. Reprinted fromGastroenterology. 2009 Oct 20 [Epub ahead of print], with permission from Elsevier. Abstract: Background & Aims. The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the early diagnosis of HCC. Methods: Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month-12) to the time of HCC diagnosis (month 0). Results: The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cut-off of 40 mAU/ml and 43% and 100%, respectively, at a cutoff of 150 mAU/ml. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/ml and 22% and 100% at a cutoff of 200 ng/ml. At month-12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients. Conclusions: Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal. COMMENTARY ON: Des-gamma-carboxy Prothrombin and Alpha fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim HY, Lee WM, Bonkovsky HL, Dienstag JL; HALT-C Trial Group. Reprinted fromGastroenterology. 2009 Oct 20 [Epub ahead of print], with permission from Elsevier. Abstract: Background & Aims. The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. The aim of this study was to compare the accuracy of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the early diagnosis of HCC. Methods: Among 1031 patients randomized in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial, a nested case-control study of 39 HCC cases (24 early stage) and 77 matched controls was conducted to compare the performance of AFP and DCP. Testing was performed on sera from 12 months prior (month-12) to the time of HCC diagnosis (month 0). Results: The sensitivity and specificity of DCP at month 0 was 74% and 86%, respectively, at a cut-off of 40 mAU/ml and 43% and 100%, respectively, at a cutoff of 150 mAU/ml. The sensitivity and specificity of AFP at month 0 was 61% and 81% at a cutoff of 20 ng/ml and 22% and 100% at a cutoff of 200 ng/ml. At month-12, the sensitivity and specificity at the low cutoff was 43% and 94%, respectively, for DCP and 47% and 75%, respectively, for AFP. Combining both markers increased the sensitivity to 91% at month 0 and 73% at month 12, but the specificity decreased to 74% and 71%, respectively. Diagnosis of early HCC was triggered by surveillance ultrasound in 14, doubling of AFP in 5, and combination of tests in 5 patients. Conclusions: Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal. The HALT-C study [[1]Di Bisceglie A.M. Shiffman M.L. Everson G.T. Lindsay K.L. Everhart J.E. Wright E.C. et al.HALT-C trial investigators. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.N Engl J Med. 2008; 359: 2429-2441Crossref PubMed Scopus (402) Google Scholar] is like the “gift that keeps on giving”, providing data for analysis after analysis. Recently the HALT-C team have addressed the issue of using alphafetoprotein and des-gamma carboxyprothombin for surveillance for HCC [[2]Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al. HALT-C Trial Group. Des-gamma-carboxy Prothrombin and Alpha fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Gastroenterology. 2009 Oct 20 [Epub ahead of print].Google Scholar]. They analysed the serum concentrations of these markers at the time of diagnosis of HCC and 12 months prior to the diagnosis. The mean values of both AFP and DCP rose in the patients with HCC over the 12 months prior to diagnosis. At diagnosis the sensitivity of a DCP measurement was 74% if the assay cut-off was 40 mAU/ml, and 43% at a cut-off of 150 mAU/ml. In contrast, 12 months prior to the diagnosis of HCC (when the HCC must have been present) the sensitivity was 43% at a cut-off of 40 mAU/mL and 3% at a cut-off of 150 mAU/ml. The results for AFP were similar, poor sensitivity at 12 months prior to the diagnosis and somewhat better sensitivity at the time of diagnosis. At the time of diagnosis, the sensitivity of AFP at a cut-off of 20 ng/ml was 61%, and at a cut-off of 200 ng/ml the sensitivity at diagnosis was 22%. At 12 months prior to diagnosis, the sensitivity of AFP at the 20 ng/ml cut-off was 47%. The authors conclude that neither AFP nor DCP are adequate for HCC surveillance. These results should be considered together with other results recently published (“the Marrero study”) in which the value of DCP was evaluated as a surveillance test [[3]Marrero J.A. Feng Z. Wang Y. Nguyen M.H. Befeler A.S. Roberts L.R. et al.Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.Gastroenterology. 2009; 137: 110-118Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar]. The authors concluded that DCP was a sensitive marker for the diagnosis of small HCC, and since HCC smaller than 2 cm should be the target of surveillance; ergo DCP was a good test for HCC surveillance. However, evaluating a test for HCC in the presence of known HCC, even small HCC, is not the same as using the test in a surveillance population. Because the study population was selected on the basis of having HCC, rather than on the basis of having for example cirrhosis, the results cannot necessarily be extrapolated to a cirrhotic population without known HCC, such as the one studied by Lok and colleagues [[2]Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al. HALT-C Trial Group. Des-gamma-carboxy Prothrombin and Alpha fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Gastroenterology. 2009 Oct 20 [Epub ahead of print].Google Scholar]. Furthermore, in a population with known HCC, further bias may be introduced by the use of AFP to make the initial diagnosis. Even with these proviso’s the Marrero study [[3]Marrero J.A. Feng Z. Wang Y. Nguyen M.H. Befeler A.S. Roberts L.R. et al.Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.Gastroenterology. 2009; 137: 110-118Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar] found that neither AFP nor DCP were very good diagnostic markers for HCC. Thus, Dr. Lok’s study [[2]Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al. HALT-C Trial Group. Des-gamma-carboxy Prothrombin and Alpha fetoprotein as Biomarkers for the Early Detection of Hepatocellular Carcinoma. Gastroenterology. 2009 Oct 20 [Epub ahead of print].Google Scholar] provides a higher level of evidence than the earlier study. These results are another nail in the coffin of serological surveillance for HCC in general and AFP surveillance in particular. Despite an obituary for AFP as a surveillance test written in 2001 [[4]Sherman M. Alphafetoprotein: an obituary.J Hepatol. 2001; 34: 603-605Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar], AFP surveillance for HCC is proving surprisingly hard to kill. More recently, an editorial accompanying the earlier study came to the same conclusion; AFP surveillance is “dead” [[5]Forner A. Reig M. Bruix J. Alpha-fetoprotein for hepatocellular carcinoma diagnosis: the demise of a brilliant star.Gastroenterology. 2009; 137: 26-29Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. The continued use of AFP is in part due to the fact that an elevated AFP is a risk factor for HCC. Patients with cirrhosis who have a persistently elevated AFP are at higher risk for HCC than similar patients in whom the AFP is not elevated. When patients undergo regular AFP surveillance and an elevated value is found this triggers further investigations. HCC is more likely to be discovered, simply because HCC will be more prevalent in a population with an elevated AFP than in population with a normal AFP. This does not make AFP a good surveillance test. The AFP is elevated because of the chronic underlying liver disease, rather than the HCC. There is good data on the lack of sensitivity of AFP for HCC surveillance [[6]Trevisani F. D’Intino P.E. Morselli-Labate A.M. Mazzella G. Accogli E. Caraceni P. et al.Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.J Hepatol. 2001; 34: 570-575Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar]. There are too many false-positives, and too many false-negatives to make this a useful test. Is DCP any better? DCP is a better serological diagnostic marker for HCC than AFP [[3]Marrero J.A. Feng Z. Wang Y. Nguyen M.H. Befeler A.S. Roberts L.R. et al.Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.Gastroenterology. 2009; 137: 110-118Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar]. It is more likely to be diagnostically elevated in patients with HCC, although a sensitivity of 74% at the time of diagnosis found in the Marrero study [[3]Marrero J.A. Feng Z. Wang Y. Nguyen M.H. Befeler A.S. Roberts L.R. et al.Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.Gastroenterology. 2009; 137: 110-118Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar] is not ideal. Unfortunately, both AFP and DCP are also risk factors for advanced disease, i.e., micro- or macrovascular invasion and/or portal vein thrombosis [7Miyaaki H. Nakashima O. Kurogi M. Eguchi K. Kojiro M. Lens culinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma.J Gastroenterol. 2007; 42: 962-968Crossref PubMed Scopus (86) Google Scholar, 8Carr B.I. Kanke F. Wise M. Satomura S. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States.Dig Dis Sci. 2007; 52: 776-782Crossref PubMed Scopus (102) Google Scholar]. They cannot therefore also be good markers for surveillance, which aims to catch early stage disease. For HCC surveillance to be effective it should detect HCC at a stage when cure is highly likely. Currently only regular ultrasonography will do this reliably. In countries where surveillance is assiduously carried out, more than 60% of HCC’s are diagnosed smaller than 3 cm. Patients at risk for HCC should undergo ultrasound surveillance at 6 monthly intervals. The AASLD guidelines to help evaluate newly discovered lesions on HCC surveillance [[9]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5123) Google Scholar] have been validated [[10]Forner A. Vilana R. Ayuso C. Bianchi L. Sole M. Ayuso J.R. et al.Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.Hepatology. 2008; 47: 97-104Crossref PubMed Scopus (818) Google Scholar] and should be used.

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