Early Detection of Hepatocellular Carcinoma: Expanding the Utility of Circulating Tumor Markers
Authors: Ju Dong Yang, Tushar Patel
Journal: Hepatology (2018)

See Article on Page 1983. Potential conflict of interest: Nothing to report. The global prevalence of hepatocellular cancer (HCC) underscores the need for effective strategies that can reduce the burden and impact of this disease. The increase in the incidence and mortality from HCC in the United States and Europe further emphasize the need for early detection to identify tumors at an early stage that are amenable to curative treatments.1 Screening and surveillance for HCC in patients with cirrhosis have been shown to improve survival.2 Guidelines from major professional societies encourage surveillance for HCC in patients with cirrhosis, advanced fibrosis, or high‐risk hepatitis B virus (HBV) infection.3 However, the approaches that are recommended for surveillance of HCC are not consistent. The recent guidelines from the American Association for the Study of Liver Diseases endorse the use of alpha‐fetoprotein (AFP) assays in conjunction with liver ultrasound.4 On the other hand, the guidelines from the European Association for the Study of the Liver support the use of liver ultrasound but not AFP or other tumor markers.3 These inconsistencies in the guidelines regarding the use of circulating biomarkers for HCC surveillance stem in part from the lack of high‐quality studies. Most of the evidence supporting the use of serum biomarkers for early HCC detection is derived from case–control studies. The use of AFP, AFP‐L3%, and des‐gamma‐carboxy prothrombin (DCP) has been assessed in Early Detection Research Network phase 2 biomarker studies.5 In this issue, Choi et al. report a carefully designed phase 3 biomarker study to evaluate the performance of serum AFP, AFP‐L3%, and DCP for the detection of early‐stage HCC.6 This nested case–control study analyzed serum that was obtained 0, 6, and 12 months prior to tumor diagnosis in 42 cases and 168 controls who were matched by age, sex, etiology, cirrhosis, and duration of follow‐up. The cases comprised mostly patients with cirrhosis, and only 7% had noncirrhotic liver disease, of whom all had HBV. Three quarters of the HCC cases were detected at a very early stage, and correspondingly >90% had tumor within Milan criteria. Most of the HCC patients (79%) had underlying chronic HBV infection, and all of these had either undetectable or suppressed (<2,000 IU/mL) HBV DNA. Moreover, 85.7% of cases had normal alanine aminotransferase (ALT) levels. Although AFP, DCP, and AFP‐L3% were similar between the cases and the control group 12 months prior to the diagnosis of HCC, they started to increase in cases but not controls between 6 and 12 months prior to tumor diagnosis. AFP had better discriminatory performance for HCC, which was further improved by the addition of AFP‐L3. Cutoff values of AFP 5 ng/mL and AFP‐L3 4% provided a sensitivity of 79% and a specificity of 87% for the detection of HCC. The sensitivity of ultrasound alone for the detection of HCC was only 49%. This is not surprising given the high proportion (75%) of very early‐stage HCC in the study population. Ultrasound performance is highly dependent on the equipment used and operator skill, and has poor performance for surveillance. When AFP and AFP‐L3% were added to liver ultrasound, the sensitivity increased to 94% while the specificity decreased from 96% to 83%. These observations are consistent with the findings from a meta‐analysis showing that addition of AFP could substantially improve the overall performance of imaging‐based surveillance.7 This study highlighted the value of performing longitudinal measurement of tumor markers and their trends for early detection of HCC in an HBV population with adequately treated hepatitis. Serially measured AFP and DCP have also been evaluated in a nested case–control study of 39 HCC cases (24 early stage) and 77 matched controls from the Hepatitis C Antiviral Long‐Term Treatment Against Cirrhosis cohort.8 In contrast to the current findings, most early‐stage HCC diagnoses were triggered by ultrasound rather than by tumor markers in this cohort, and AFP and DCP were noted to have suboptimal performance. Active viremia and hepatic injury can elevate AFP in the absence of HCC, and this could have undermined the performance of serum‐based tests. AFP is more accurate for the diagnosis of HCC when ALT is normal.9 However, the performance of serum biomarkers for surveillance and detection of very early‐stage tumor in patients with minimal hepatic injury has not been investigated. The study has several limitations. The statistical power is limited by the relatively small number of HCC cases, which is consequently reflected in the wide 95% confidence intervals for both sensitivity and specificity. Surprisingly, DCP was not shown to have an additive role to AFP and AFP‐L3%. The use of DCP for surveillance in conjunction with AFP and AFP‐L3 is common in practice and endorsed by clinical practice guidelines in China and Japan. All three tumor markers are incorporated in the GALAD (gender, age, AFP‐L3, AFP, and DCP) score, which has been validated extensively.10 DCP may perform better in the setting of advanced tumor stage with portal vein invasion. Could the findings in the study by Choi et al. represent a false‐negative observation? An assessment in a larger cohort would be necessary to evaluate this possibility and to define the additive utility of DCP for HCC surveillance along with AFP and AFP‐L3%. A notable limitation of this study is the lack of external validation of the results. In this regard, we note the logistical challenges in conducting longitudinal surveillance biomarker studies in patients with cirrhosis. The incidence of HCC decreases substantially in patients with cirrhosis and controlled viremia or nonviral etiology, raising the question of whether or not the risk of HCC is sufficiently high to warrant surveillance. Validation phase 3 biomarker studies are likely to be costly and require multicenter efforts but will be eagerly awaited. Until that time, and with the other study limitations noted, it is premature to adopt the proposed cutoffs into routine practice. Validation in patients with underlying liver disease other than chronic HBV infection will be necessary prior to incorporating these findings and cutoffs into routine surveillance practice for all patients with cirrhosis. In particular, assessment in patients with nonalcoholic steatohepatitis will be relevant because of the suboptimal performance of ultrasound for surveillance in this population due to the high prevalence of obesity. Moreover, false‐positive results can counteract the impact of gains in detection rate and increase the cost of surveillance. Once the accuracy of longitudinal assessment of serum biomarkers for surveillance has been established, the cost‐effectiveness of their use should be determined prior to embracing their use in clinical practice.