Elsevier

Contemporary Clinical Trials

Volume 76, January 2019, Pages 49-54
Contemporary Clinical Trials

Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute’s Early Detection Research Network

https://doi.org/10.1016/j.cct.2018.11.008Get rights and content

Abstract

Background

Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity.

Methods

The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository.

Results

The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis.

Conclusions

The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers.

Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.

Introduction

Hepatocellular carcinoma (HCC) is a growing cause of cancer-related death in the United States [1]. Among all malignancies, HCC presented the largest increase in incidence over the past decade [[1], [2], [3]]. The National Cancer Institute Surveillance Epidemiology and End Results database, U.S. Vital Statistics, and the Department of Veteran Administration showed the increasing incidence of HCC can be attributed primarily to the high prevalence of hepatitis C virus (HCV) and the progressive nature of liver disease to cirrhosis [[4], [5], [6]]. Chronic HCV, hepatitis B (HBV), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and autoimmune diseases can all progress to cirrhosis. As such, patients with these conditions are at high risk of developing HCC, with annual incidence rates up to 2% per year [5,6]. Despite the highly effective oral direct-acting antiviral (DAA) regimens for HCV, a significant percentage of these patients have cirrhosis and remain at risk for HCC [7]. While convincing evidence suggests achieving sustained viral response (SVR) decreases the risk of developing initial HCC in patients with HCV cirrhosis, there remain conflicting data on the effect of HCV treatment on the recurrence of HCC in patients with cirrhosis [[8], [9], [10]]. Though HBV treatment with oral nucleos(t)ides is known to decrease HCC risk, treated patients especially with cirrhosis remain at significant risk for HCC [[11], [12], [13], [14]]. NAFLD must be seriously considered in the context of HCC surveillance, as it has become the leading cause of chronic liver disease in our country [15,16]. Patients with NAFLD are at an increased risk of developing HCC, even if they do not have cirrhosis [16,17].

Surveillance guidelines for HCC include twice-yearly ultrasound (US) imaging with or without assessment of the biomarker alpha-fetoprotein (AFP) [18,19]. However, there have been limitations with regard to the sensitivity and specificity of AFP and US [20,21]. Preliminary data suggest that a combination of AFP >10 ng ml−1 or a composite AFP index achieves adequate sensitivity for early detection of HCC [22]. Additional biomarkers that have been evaluated and used in clinical practice include AFP-L3 and des-carboxy prothrombin (DCP), but these have not demonstrated superiority over AFP as single markers [20,23]. The GALAD (Gender, Age, AFP-L3, AFP, DCP) model combined simple demographic data with these biomarkers in an attempt to improve upon the AFP sensitivity and specificity [24,25]. This model was recently validated in a large cohort for the diagnosis of HCC, distinguished from non-HCC malignancy, and warrants prospective clinical studies for its role in HCC surveillance [25]. Investigators have also evaluated other biomarkers including GP73, kininogen, osteopontin, and certain glycoproteins, but none of these have been validated in clinical practice for HCC surveillance [26,27].

Given the continued rise in incidence and mortality of HCC, along with the limitations of the current surveillance strategy, the development of improved methods for early detection are of utmost importance. To that end, the NIH-sponsored Early Detection Research Network (EDRN) continues to support multi-center studies focused on developing novel biomarkers and further examining the risk factors, incidence, and course of HCC in the US population.

Section snippets

Des-Carboxy Prothrombin Validation (DCP-V) case/control study

In the year 2000, the EDRN collaborative group was established to assess the role of then available markers for the detection of early stage HCC. An EDRN Phase II case/control study on the validation of DCP as a biomarker for detecting incipient HCC (the “DCP-V" study) was initiated and comprised of two well defined groups of patients with cirrhosis. The first group included patients with cirrhosis and HCC (cases); the second included patients with cirrhosis without detected HCC (controls). The

Discussion

It has been widely acknowledged that the presence of cirrhosis, regardless of etiology, is the leading risk factor for the development of HCC [[4], [5], [6]]. Evidence supporting the presently published incidence rates in the US, as well as the current screening and surveillance recommendations, were compiled from patient populations with cirrhosis primarily caused by untreated HCV [[5], [6], [7]]. Further, most studies describing the incidence of HCC after successful HCV therapy were

Declaration of conflicting interests

Neehar D. Parikh serves on the advisory board for Bayer and Eisai Co, Ltd., and as a consultant to Bristol-Myers Squibb and Exelixis, Inc. The other authors have no disclosures.

Funding

This work was supported by the National Cancer Institute of the National Institutes of Health under Award Number U24CA086368.

Grant support

This study is supported by the National Cancer Institute of the National Institutes of Health's Award Number U24CA086368.

Acknowledgements

We appreciate the generous support from the National Cancer Institute. This publication was supported under Award Number U24CA086368. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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