Protein Biomarker in Hepatocellular Carcinoma

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Terminated

CT.gov ID

NCT00465842

Collaborator

Singapore Cancer Society (Other)

211

Enrollment

Location

85.8

Actual Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Hepatocellular carcinoma (HCC) is the fifth commonest cancer in the world with poor prognosis, as the annual mortality is almost equivalent to the incidence. This is mainly due to late diagnosis and co-morbid liver dysfunction. HCC is prevalent in our region than in the West due to prevalent Hepatitis B infection and carriers. At the time of diagnosis, only 10 - 20% of HCC patients are candidates for liver resection or transplantation. Almost 40-50% of patients have such poor liver function and co-morbid conditions that only supportive cares are offered. Thus the median survival time is 18-24 months for resectable disease, 6 months for unresectabe disease and 3 months for metastatic disease.

Current screening methods for HCC in high risk patients depend on alpha-fetoprotein (AFP) and ultrasound of the liver. Neither test is sensitive or specific enough for early detection. Therefore, early diagnosis with novel protein biomarkers is needed urgently and may provides hope to improve treatment outcome.

Our preliminary study in 49 HCC patients have identified several proteins such as truncated complement C3a, albumin, B2 microglobulin, may be potentially helpful in early diagnosis. We have started a large prospective and longitudinal study in July 2006, with nearly 100 patients accrued. This application is to extend and expand our current study. We aim to (i) identify and validate novel protein biomarkers for early diagnosis of HCC (ii) conduct longitudinal proteomics with most up-to-date methods to discover new biomarker for early detection and prognostication of HCC (iii) set up gene and plasma depository and clinical database for HCC in collaboration with Singapore Tissue Network.

Condition or Disease	Intervention/Treatment	Phase
Normal Volunteers Hepatitis Liver Cirrhosis Hepatocellular Carcinoma

Detailed Description

Up to 40% of HCC patients have normal AFP. Moreover, AFP can also be elevated in patients with cirrhosis or exacerbation of chronic hepatitis. Prospective studies evaluating the value of AFP in HCC surveillance have reported sensitivities of 39-64%, specificity of 76-91% and positive predictive values of 9 -32% 9-11.

Recently, a small handful of biomarkers were identified in the blood of 49 HCC patients by SELDI / MS proteomic analysis of their blood with specificity and sensitivity both at 90% 12, 13. These were truncated complement C3a, albumin, B2 microglobulin, and histidine-rich glycoprotein. In addition, insulin growth factor (IGF) and its binding protein have been shown to be novel biomarkers of HCC 14-17. A larger prospective study is necessary to validate these findings.

Other investigators have also used Surface-enhanced laser desorption / ionization time-of-flight mass spectrometry (SELDI) to study proteomics in HCC. Most of the studies included small numbers of patients and did not include independent test set or report on reproducibility most of the time. Thus, controversies continue on both the technology of SELDI and validation of the findings. Nevertheless, Ward et al reported that Kappa and Lumda immunoglobulin light chains were elevated by an average pf 50% in the serum of HCC patients (p < 0.001, sensitivity 94%, specificity 86%) with Hepatitis C related cirrhosis 18. Schwegler et al reported that SELDI-TOF MS profiling of serum can distinguish chronic Hepatitis C from HCV- related HCC with a sensitivity of 61% and a specificity of 76%. Sensitivity and specificity can be improved with the addition of AFP, des-gamma carboxyprothrombin, and GP73 19. Other reports also indicated potential marker of heat-shock protein 27 20 and complement C3a 21. However, all studies lack prospective and longitudinal follow-up with multiple serum samples from same patient. Our trial is designed to test the changes of proteomic overtime to identify the earliest possible biomarkers for HCC.

Study Design

Study Type:

Observational

Actual Enrollment :

211 participants

Observational Model:

Other

Time Perspective:

Prospective

Official Title:

Protein Biomarkers for Early Detection and Prognostication in Hepatocellular Carcinoma (HCC)

Actual Study Start Date :

Jun 20, 2006

Actual Primary Completion Date :

Aug 14, 2013

Actual Study Completion Date :

Aug 14, 2013

Arms and Interventions

Arm	Intervention/Treatment
A - Normal Volunteers Normal volunteers without any history of liver disease and with normal liver functions test (LFT), including total protein/Albumin, LDH, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin and do not belong to group B. Volunteers will be screened using questionnaires. Those deemed suitable will then be asked to have the blood test done. All blood tests are done free of charge to subjects.
B - Hepatitis B or C carriers with normal liver functions
C - Hepatitis B or C carriers with abnormal liver functions
D - Liver Cirrhosis Liver cirrhosis, proven by liver biopsy or on clinical evidences, such as varices on CT scan indicative of portal hypertension.
E - Hepatocellular Carcinoma (HCC) with Resection HCC patients with resection.
F - Unresectable HCC Unresectable HCC patients with treatment
G - Malignant HCC HCC patients with active malignant disease and only palliative care are offered.

Outcome Measures

Primary Outcome Measures

Number of participants with presence of serum protein markers [Day 1]
Number of participants with truncated complement C3a, albumin, B2-microglobulin and histidine-rich glycoprotein, IGF-I, and IGF-II on first blood sample.

Secondary Outcome Measures

Number of participants with hepatocellular carcinoma (HCC) with presence of protein markers. [up to 5 years]
To study the prospective and longitudinal value of these protein markers in detecting HCC by regular measurement of these proteins and follow up with routine clinical practice in high-risk patients.
Number of participants with presence of serum protein markers with resectable and unrsectable HCC. [up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Group A: Normal volunteers without any history of liver disease and with normal liver functions test (LFT), including total protein/Albumin, LDH, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin and do not belong to group B. Volunteers will be screened using questionnaires. Those deemed suitable will then be asked to have the blood test done. All blood tests are done free of charge to subjects.
Group B: Hepatitis B or C carriers with normal liver functions.
Group C: Hepatitis B or C carriers with abnormal liver functions.
Group D: Liver cirrhosis, proven by liver biopsy or on clinical evidences, such as varices on CT scan indicative of portal hypertension.
Group E: HCC patients with resection.
Group F: Unresectable HCC patients with treatment.
Group G: HCC patients with active malignant disease and only palliative care are offered.
Signed Informed Consent

-≥ 18 years of age

In this trial, diagnosis of HCC is established with either (a) known hepatitis B or C carrier, and space occupying lesion(s) in the liver and AFP > 400ng/ml or (b) cytological or histological confirmation by biopsy