Original article
Pancreas, biliary tract, and liver
Improved Detection of Hepatocellular Carcinoma by Using a Longitudinal Alpha-Fetoprotein Screening Algorithm

https://doi.org/10.1016/j.cgh.2015.07.049Get rights and content

Background & Aims

Hepatocellular carcinoma (HCC) has limited treatment options when diagnosed at advanced stages; therefore, early detection is critical to reduce mortality. There is disagreement about the value of α-fetoprotein (AFP) in HCC surveillance. We aim to improve the sensitivity of AFP in HCC surveillance by using an algorithm that incorporates screening history to define patient-specific thresholds for positive a screen.

Methods

De-identified data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, which enrolled 1050 patients with hepatitis C and advanced fibrosis or cirrhosis who were prospectively followed every 3–6 months, were analyzed. AFP was assayed at each visit, and ultrasonography was performed every 6–12 months. A panel adjudicated the diagnosis of HCC. A parametric empirical Bayes (PEB) screening algorithm, which incorporates screening history, was compared with a single threshold approach for interpreting AFP results.

Results

During a median follow-up of 80 months, 88 patients (48 of 427 with cirrhosis and 40 of 621 with advanced fibrosis) were diagnosed with HCC. PEB improved the sensitivity of AFP for detecting all HCC from 60.4% to 77.1% (P < .0005) in patients with cirrhosis and from 72.5% to 87.5% (P = .0015) in patients with advanced fibrosis, when the false-positive rate among all screenings was set at 10%. PEB algorithm detected HCC 1.7–1.9 years earlier in the cirrhosis group and 1.4–1.7 years earlier in the advanced fibrosis group, compared with single threshold approach.

Conclusions

PEB increases the sensitivity of AFP testing and detects HCC earlier among hepatitis C patients with advanced fibrosis or cirrhosis. These data should prompt a reevaluation of how AFP is used in combination with ultrasound in HCC surveillance.

Section snippets

Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial Design

The HALT-C trial enrolled patients with chronic hepatitis C in a randomized controlled trial in which the patients had to have at least stage 3 fibrosis (bridging fibrosis or cirrhosis) by the Ishak scoring system (range, 0–6) and a history of failure to respond to previous interferon-based therapy. All patients had radiologic imaging to exclude HCC before enrollment. The trial aimed to determine whether long-term low-dose pegylated interferon therapy was a safe and efficacious treatment in

Data Description

Of the 1050 patients in the HALT-C trial, 1048 patients with HCC outcome data and serial AFP measurements were included in this analysis. On the basis of the baseline biopsy, 427 were diagnosed with cirrhosis and 621 with advanced fibrosis. Among patients with cirrhosis at baseline biopsy, 361 had more than 12 months of follow-up from enrollment and were not diagnosed with HCC during a median follow-up period of 78 months (range, 15–109 months), and 48 had confirmed HCC during study follow-up.

Discussion

By using data from the HALT-C trial, a large prospective trial involving more than 1000 patients with advanced fibrosis or cirrhosis caused by chronic hepatitis C infection who were followed for a median of 80 months, we observed statistically significant gains in the sensitivity of AFP when serial biomarker measurements were incorporated into the screening algorithm. In this study, we found that when specificity at the screening level was set at 90%, ie, FPR of 10%, the PEB algorithm increased

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    Citation Excerpt :

    Patients diagnosed in early stages have more treatment options available and improved outcomes than those diagnosed at later stages, for whom palliative care is often the only option.18,19 However, HCC is infrequently detected early.17,20-22 Late diagnosis is partly related to the lack of HCC symptoms in the early stages.23-25

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Conflicts of interest This author discloses the following: Anna S. F. Lok was one of the HALT-C investigators. The remaining authors disclose no conflicts.

Funding Kim-Anh Do and Ziding Feng are partially supported by a Cancer Center Support Grant (NCI grant P30CA016672). Ziding Feng is partially supported by EDRN grant (NCI grant U24086368). Nabihah Tayob is partially supported by start-up and incentive funds to Kim-Anh Do and Ziding Feng.

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