Notice of Availability of Serum Samples and Research Support for Validation of Hepatocellular Carcinoma (HCC) Biomarkers

Notice Number: NOT-DK-09-016

Key Dates
Release Date: August 20, 2009

Issued by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (


NIDDK in collaboration with National Cancer Institute through its Early Detection Research Network announces the availability of serum samples and research funds for validation of biomarkers for hepatocellular carcinoma among study participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. 

HALT-C is an NIH sponsored, multicenter, randomized clinical trial of 1050 patients to determine if long-term treatment with low-dose peginterferon alfa-2a could prevent progression of liver disease among persons with chronic hepatitis C who had not cleared virus on short-term treatment and had histologically advanced liver disease.  Full description of the trial and its results have been published (Lee WM et al. Evolution of the HALT-C trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon non-responders. Control Clin Trials 2004;25:472-496; Di Bisceglie AM et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429-41). Additional information, including a catalogue of samples at the HALT-C repository, can be found on the HALT-C web site

All patients had a battery of biochemical, serological and virological studies performed at baseline, as well as a liver biopsy. Thereafter, all patients (treated and untreated) were evaluated at 3 month intervals by history, physical examination, hematological, biochemical, serological and virological parameters. All patients were requested also to undergo repeat liver biopsies 1.5 years and 3.5 years after beginning treatment. Because HCC was one of the primary outcomes, serum alpha-fetoprotein was measured at each visit and an ultrasound examination was performed at week 24 and at months 12, 24, 36, 48, 60 and every 6 months thereafter, seeking evidence of incipient HCC. At each visit, serum samples were sequestered and placed in the HALT-C repository for future research purposes.  Currently, there are almost 225,000 samples in the repository, consisting primarily of sera, but also including plasma and whole blood, PBMCs, DNA, and liver tissue.

Confirmation of HCC development, together with the extensive collection of serum samples stored in the HALT-C tissue repository, offers the opportunity to define the value of currently known biomarkers for surveillance of HCC, with the hope of establishing indicators for its early diagnosis.  More effective biomarkers capable of identifying early HCC are clearly needed. For this purpose, a reference set of sera from patients who had a definite diagnosis of HCC, together sera from individuals without evidence of HCC, are available for research to establish the value of newer biomarkers of HCC.

At scheduled quarterly or semi-annual intervals, patients underwent clinical evaluation that included systematic testing for the presence of liver cancer.   Following diagnosis of HCC at the local site, at least 2 independent reviewers determined whether clinical evidence supported the diagnosis.  Cases of HCC were deemed definite or presumed according to accepted criteria by at least two independent investigators.   Stored samples are available from approximately 50 cases of HCC, of whom about 85% are considered definite.

Specimen collection began upon initiation of trial enrollment in 2000 and has continued to this date. At each patient visit, serum was collected and aliquoted and subsequently frozen at –80oC for long-term storage at a central repository. Specimens will be provided in 200 µl aliquots that have undergone one freeze thaw cycle.

The use of HALT-C samples for the evaluation of biomarkers for HCC fits within the current framework for the establishment and testing of biomarkers.  Thus, evaluation of cancer biomarkers may proceed through five phases to establish clinical utility (Pepe MS, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 2001;93:1054-106).  The HALT-C samples will be available for Phase II studies to assess the ability of the biomarker to distinguish subjects with cancer from at risk subjects without cancer and for Phase III to evaluate the capacity of biomarkers to detect preclinical disease. 

Samples from cases and controls will be made available in two steps according to the definitions for Phase II and Phase III biomarker studies.   In the first step, serum samples assembled at or close to the time of diagnosis of HCC will be provided together with up to 2 serum samples from study participants who were not known to develop HCC but shared clinical characteristics (control samples).  The controls would be selected according to histological fibrosis stage (bridging fibrosis or cirrhosis) and treatment assignment (peginterferon or no treatment) in accordance with the design of the HALT-C trial.  The samples will be masked as to source (HCC case or control).  In order to proceed to the next step, the tested biomarker must perform at least as well as or must complement the standard serum test of AFP that has been evaluated in the study.  In the second step, masked samples obtained between 2 and 6 time points prior to the diagnosis of HCC will be provided together with samples from a suitable number of patients who were not known to have developed cancer (controls).   The HALT-C data coordinating center would perform the data analyses.

The detailed protocol for requesting access to these samples will be available on the EDRN website (


Direct program/scientific related questions or inquiries to:

James Everhart, M.D., M.P.H.
Chief, Epidemiology and Clinical Trials Branch
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 655
6707 Democracy Boulevard, MSC 5450
Bethesda, MD 20892-5450
Phone: (301) 594-8878
Fax: (301) 480-8300

Direct submission and review questions or inquiries to:

Jo Ann Rinaudo, Ph.D.
National Cancer Institute
Early Detection Research Network
Executive Plaza North, Room 3143
6130 Executive Blvd, MSC 7362
Rockville, MD 20892-7362
Phone: (301) 435-1594

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