Combining Biomarkers (AFP, AFP-L3, and PIVKA-II) and Image Tools for Early Detection of Hepatocellular Carcinoma

Study Overview
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Brief Summary
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In this study, three biomarkers tests (AFP, AFP-L3 and PIVKA-II) and abdominal sonography or CT scans are performed every 6 months to detect hepatocellular carcinoma (HCC) early in patients with cirrhosis, a high-risk group of HCC. The aim of this study is to confirm the early HCC diagnosis rate in patients with cirrhosis and compare the detection efficacy between tests.

Detailed Description
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Early diagnosis of HCC is the most important factor in improving the prognosis of the disease. A surveillance test for early diagnosis of HCC in Korea is to perform alfa fetoprotein (AFP) and abdominal sonography every 6-months in high-risk groups. However, the detection rate of HCC using AFP and abdominal sonography is very low. There are several reports that the combination of the multiple biomarker tests including AFP, AFP L3, and PIVKA-II increased the early HCC detection only one test. Therefore, in the surveillance test for HCC, the combination of three tests with sonography would be helpful in the early diagnosis of HCC. However, there was few prospective large-scale studies about this issue. Compared with abdominal sonography, contrast-enhanced CT or MRI is more useful in finding intrahepatic lesions of liver cirrhosis. However, there is no evidence data on combining sono/CT and biomarkers could improve the diagnosis for early HCC. Thus, it is essential to verify this prospectively in the real clinical practices to make recommendations based on a high level of evidence in the future. The investigators are conducting a prospective study which examines three biomarker tests and sonography every six months and contrast-enhanced CT annually for HCC surveillance in patients with cirrhosis.

Official Title
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Clinical Usefulness of Combining Biomarkers (AFP, AFP-L3, and PIVKA-II) With Abdominal Sonography or Computed Tomography for Early Detection of Hepatocellular Carcinoma

Conditions
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Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance

Intervention / Treatment
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* Diagnostic Test: AFP-L3
* Diagnostic Test: AFP
* Diagnostic Test: PIVKA-II
* Diagnostic Test: Sonography
* Diagnostic Test: CT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with liver cirrhosis meeting one of the followings: i. Histologically confirmed liver cirrhosis ii. Imaging findings with liver cirrhosis (liver surface undulation, irregularity, or nodularity by US, CT, or MRI) plus one of followings: liver stiffness measurement ≥ 12.5 kilopascal, esophago-gastric varices, thrombocytopenia (<120,000/mm3), hypoalbuminemia (<3.5 g/dL), splenomegaly ≥12 cm) iii. Imaging findings with liver cirrhosis together with biomarkers suggesting liver cirrhosis (APRI ≥2.0 or fibrosis-4 ≥3.6) iv. Imaging findings with liver cirrhosis with history of hepatic decompensation (ascites, esophago-gastric variceal bleeding, jaundice, hepatic encephalopathy)) Expected survival more than 1 year Child Pugh score 5-10 at the time of enrollment Serum creatinine ≤1.5mg/dL Age between 19 and 75 years old No significant underlying medical illness affecting patient's survival Patients available for regular follow-up according to the study protocol Exclusion Criteria: History of HCC AFP >20 ng/mL Hepatic nodule ≥ 1 cm by US or CT Exceptionally, nodules showing characteristic features of benign lesion such as hemangioma or pathologically conformed benign lesion are permitted for study inclusion. Hepatic nodule less than 1 cm on US but imaging findings suggesting HCC by contrast enhanced US, CT, or MRI Child-Pugh score ≥ 11 History of liver transplantation Expecting liver transplantation within 1 year Hypersensitivity on CT contrast dye Any contraindication for CT Not able to perform abdominal US Other uncontrolled malignancy Patients taking warfarin

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Intervention Model: Single Group Assignment
Interventional Model Description: Patients with cirrhosis will receive the surveillance test using three biomarker tests and sonography every six months and contrast-enhanced CT annually
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Surveillance<br>All participants will be examined with three biomarker tests and sonography every six months and contrast-enhanced CT annually. | Diagnostic Test: AFP-L3<br>* AFP-L3 will be tested using serum sample every 6 months.<br>* Other names: Lens culinaris agglutinin-reactive fraction of AFP;Diagnostic Test: AFP<br>* AFP will be tested using serum sample every 6 months.<br>* Other names: Alpha fetoprotein;Diagnostic Test: PIVKA-II<br>* PIVKA-II will be tested using serum sample every 6 months.<br>* Other names: des-gamma-carboxy prothrombin;Diagnostic Test: Sonography<br>* Sonography will be tested by experts every 6 months.<br>* Other names: US;Diagnostic Test: CT<br>* Contrast-enhanced CT will be tested annually.<br>* Other names: Computed tomography;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCC occurrence | Detection of HCC occurrence by three biomarkers and two image modalities | 3 years after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early HCC occurrence | Detection of HCC less than 2cm | 3 years after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance, AFP-L3, AFP, PIVKA-II, Sonography, CT