search
Back to results

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

Primary Purpose

Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance

Status
Recruiting
Phase
Not Applicable
Locations
Korea, Republic of
Study Type
Interventional
Intervention
AFP-L3
AFP
PIVKA-II
Sonography
CT
Sponsored by
Korea University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Liver Cirrhosis focused on measuring Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance, AFP-L3, AFP, PIVKA-II, Sonography, CT

Eligibility Criteria

19 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Korea University Ansan HospitalRecruiting
  • The Catholic University of Korea Uijeongbu St.Mary's HospitalRecruiting
  • Keimyung University Dongsan Medical CenterRecruiting
  • Inje University SangGye Paik HospitalRecruiting
  • Korea University Anam HospitalRecruiting
  • Seoul National University HospitalRecruiting
  • Severance HospitalRecruiting
  • Soonchunhyang University Seoul HospitalRecruiting
  • Hanyang University HospitalRecruiting
  • Konkuk University HospitalRecruiting
  • Asan Medical CenterRecruiting
  • Samsung Medical CenterRecruiting
  • The Catholic University of Korea Seoul St.Mary's HospitalRecruiting
  • Chung-Ang University HosptialRecruiting
  • Korea University Guro HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Surveillance

Arm Description

All participants will be examined with three biomarker tests and sonography every six months and contrast-enhanced CT annually.

Outcomes

Primary Outcome Measures

HCC occurrence
Detection of HCC occurrence by three biomarkers and two image modalities

Secondary Outcome Measures

Early HCC occurrence
Detection of HCC less than 2cm

Full Information

First Posted
May 20, 2020
Last Updated
May 30, 2020
Sponsor
Korea University
Collaborators
Korea University Ansan Hospital, Soonchunhyang University Hospital, Korea University Guro Hospital, The Catholic University of Korea, Samsung Medical Center, Asan Medical Center, Korea University Anam Hospital, Keimyung University Dongsan Medical Center, Severance Hospital, Hanyang University, Konkuk University Hospital, Seoul National University Hospital, Inje University, Chung-Ang University Hosptial, Chung-Ang University College of Medicine
search

1. Study Identification

Unique Protocol Identification Number
NCT04414956
Brief Title
Combining Biomarkers (AFP, AFP-L3, and PIVKA-II) and Image Tools for Early Detection of Hepatocellular Carcinoma
Official Title
Clinical Usefulness of Combining Biomarkers (AFP, AFP-L3, and PIVKA-II) With Abdominal Sonography or Computed Tomography for Early Detection of Hepatocellular Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2016 (Actual)
Primary Completion Date
June 30, 2023 (Anticipated)
Study Completion Date
February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Korea University
Collaborators
Korea University Ansan Hospital, Soonchunhyang University Hospital, Korea University Guro Hospital, The Catholic University of Korea, Samsung Medical Center, Asan Medical Center, Korea University Anam Hospital, Keimyung University Dongsan Medical Center, Severance Hospital, Hanyang University, Konkuk University Hospital, Seoul National University Hospital, Inje University, Chung-Ang University Hosptial, Chung-Ang University College of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance
Keywords
Liver Cirrhosis, Hepatocellular Carcinoma, Surveillance, AFP-L3, AFP, PIVKA-II, Sonography, CT

7. Study Design

Primary Purpose
Screening
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
1418 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Surveillance
Arm Type
Other
Arm Description
All participants will be examined with three biomarker tests and sonography every six months and contrast-enhanced CT annually.
Intervention Type
Diagnostic Test
Intervention Name(s)
AFP-L3
Other Intervention Name(s)
Lens culinaris agglutinin-reactive fraction of AFP
Intervention Description
AFP-L3 will be tested using serum sample every 6 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
AFP
Other Intervention Name(s)
Alpha fetoprotein
Intervention Description
AFP will be tested using serum sample every 6 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
PIVKA-II
Other Intervention Name(s)
Protein induced by vitamin K absence or antagonist-II, des-gamma-carboxy prothrombin
Intervention Description
PIVKA-II will be tested using serum sample every 6 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
Sonography
Other Intervention Name(s)
Ultrasound, US
Intervention Description
Sonography will be tested by experts every 6 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
CT
Other Intervention Name(s)
Computed tomography
Intervention Description
Contrast-enhanced CT will be tested annually.
Primary Outcome Measure Information:
Title
HCC occurrence
Description
Detection of HCC occurrence by three biomarkers and two image modalities
Time Frame
3 years after enrollment
Secondary Outcome Measure Information:
Title
Early HCC occurrence
Description
Detection of HCC less than 2cm
Time Frame
3 years after enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hyung Joon Yim, MD,PhD
Phone
+82-31-412-6565
Email
gudwns21@korea.ac.kr
First Name & Middle Initial & Last Name or Official Title & Degree
Soon Ho Um, MD,PhD
Phone
+82-2-920-5019
Email
umsh@korea.ac.kr
Facility Information:
Facility Name
Korea University Ansan Hospital
City
Ansan
State/Province
Gyeonggi-do
ZIP/Postal Code
15355
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hyung Joon Yim
Phone
+82-31-412-6565
Email
gudwns21@korea.ac.kr
First Name & Middle Initial & Last Name & Degree
Tae Hyung Kim
Phone
+82-31-412-4832
Email
lacid@korea.ac.kr
Facility Name
The Catholic University of Korea Uijeongbu St.Mary's Hospital
City
Uijeongbu
State/Province
Gyeonggi-do
ZIP/Postal Code
11765
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Changwook Kim
Facility Name
Keimyung University Dongsan Medical Center
City
Daegu
ZIP/Postal Code
42601
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Byoungkuk Jang
Facility Name
Inje University SangGye Paik Hospital
City
Seoul
ZIP/Postal Code
01757
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eileen L. Yoon
Email
mseileen80@gmail.com
Facility Name
Korea University Anam Hospital
City
Seoul
ZIP/Postal Code
02841
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Soon Ho Um
Phone
+82-2-920-6555
Email
umsh@korea.ac.kr
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yunjoon Kim
Facility Name
Severance Hospital
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Doyoung Kim
Facility Name
Soonchunhyang University Seoul Hospital
City
Seoul
ZIP/Postal Code
04401
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jae Young Jang
Email
jyjang@schmc.ac.kr
Facility Name
Hanyang University Hospital
City
Seoul
ZIP/Postal Code
04763
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DaeWon Jun
Facility Name
Konkuk University Hospital
City
Seoul
ZIP/Postal Code
05030
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wonhyeok Choe
Facility Name
Asan Medical Center
City
Seoul
ZIP/Postal Code
05505
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Youngseok Yim
Facility Name
Samsung Medical Center
City
Seoul
ZIP/Postal Code
06351
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yonghan Paik
Facility Name
The Catholic University of Korea Seoul St.Mary's Hospital
City
Seoul
ZIP/Postal Code
06591
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeong Won Jang
Facility Name
Chung-Ang University Hosptial
City
Seoul
ZIP/Postal Code
06973
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hyungjoon Kim
Facility Name
Korea University Guro Hospital
City
Seoul
ZIP/Postal Code
08308
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ji Hoon Kim
Email
kjhhepar@naver.com

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21992124
Citation
El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011 Sep 22;365(12):1118-27. doi: 10.1056/NEJMra1001683. No abstract available.
Results Reference
background
PubMed Identifier
25918260
Citation
Korean Liver Cancer Study Group (KLCSG); National Cancer Center, Korea (NCC). 2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver. 2015 May 23;9(3):267-317. doi: 10.5009/gnl14460.
Results Reference
background
PubMed Identifier
25852267
Citation
Yim HJ, Suh SJ, Um SH. Current management of hepatocellular carcinoma: an Eastern perspective. World J Gastroenterol. 2015 Apr 7;21(13):3826-42. doi: 10.3748/wjg.v21.i13.3826.
Results Reference
background
PubMed Identifier
22424438
Citation
European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012 Apr;56(4):908-43. doi: 10.1016/j.jhep.2011.12.001. No abstract available. Erratum In: J Hepatol. 2012 Jun;56(6):1430.
Results Reference
background
PubMed Identifier
26352789
Citation
Yim SY, Seo YS, Jung CH, Kim TH, Lee JM, Kim ES, Keum B, Jong YK, An H, Kim JH, Yim HJ, Kim DS, Jeen YT, Yeon JE, Lee HS, Chun HJ, Byun KS, Um SH, Kim CD, Ryu HS. The management and prognosis of patients with hepatocellular carcinoma: what has changed in 20 years? Liver Int. 2016 Mar;36(3):445-53. doi: 10.1111/liv.12960. Epub 2015 Oct 12.
Results Reference
result
PubMed Identifier
18849011
Citation
Sterling RK, Jeffers L, Gordon F, Venook AP, Reddy KR, Satomura S, Kanke F, Schwartz ME, Sherman M. Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2009 Jan;7(1):104-13. doi: 10.1016/j.cgh.2008.08.041. Epub 2008 Sep 17.
Results Reference
result
PubMed Identifier
1694805
Citation
Taketa K, Sekiya C, Namiki M, Akamatsu K, Ohta Y, Endo Y, Kosaka K. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology. 1990 Aug;99(2):508-18. doi: 10.1016/0016-5085(90)91034-4.
Results Reference
result
PubMed Identifier
7693340
Citation
Taketa K, Endo Y, Sekiya C, Tanikawa K, Koji T, Taga H, Satomura S, Matsuura S, Kawai T, Hirai H. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res. 1993 Nov 15;53(22):5419-23.
Results Reference
result
PubMed Identifier
11851836
Citation
Oka H, Saito A, Ito K, Kumada T, Satomura S, Kasugai H, Osaki Y, Seki T, Kudo M, Tanaka M; Collaborative Hepato-Oncology Study Group of Japan. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein. J Gastroenterol Hepatol. 2001 Dec;16(12):1378-83. doi: 10.1046/j.1440-1746.2001.02643.x.
Results Reference
result
PubMed Identifier
16848811
Citation
Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, Toshikuni N, Tanaka H, Miyake Y, Matsumoto E, Shiratori Y. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol. 2006 Sep;101(9):2038-43. doi: 10.1111/j.1572-0241.2006.00681.x. Epub 2006 Jul 18.
Results Reference
result
PubMed Identifier
23372355
Citation
Choi JY, Jung SW, Kim HY, Kim M, Kim Y, Kim DG, Oh EJ. Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP. World J Gastroenterol. 2013 Jan 21;19(3):339-46. doi: 10.3748/wjg.v19.i3.339.
Results Reference
result
PubMed Identifier
19391065
Citation
Yoon YJ, Han KH, Kim DY. Role of serum prothrombin induced by vitamin K absence or antagonist-II in the early detection of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Scand J Gastroenterol. 2009;44(7):861-6. doi: 10.1080/00365520902903034.
Results Reference
result
PubMed Identifier
25852278
Citation
Seo SI, Kim HS, Kim WJ, Shin WG, Kim DJ, Kim KH, Jang MK, Lee JH, Kim JS, Kim HY, Kim DJ, Lee MS, Park CK. Diagnostic value of PIVKA-II and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2015 Apr 7;21(13):3928-35. doi: 10.3748/wjg.v21.i13.3928.
Results Reference
result
PubMed Identifier
26340708
Citation
Lim TS, Kim DY, Han KH, Kim HS, Shin SH, Jung KS, Kim BK, Kim SU, Park JY, Ahn SH. Combined use of AFP, PIVKA-II, and AFP-L3 as tumor markers enhances diagnostic accuracy for hepatocellular carcinoma in cirrhotic patients. Scand J Gastroenterol. 2016 Mar;51(3):344-53. doi: 10.3109/00365521.2015.1082190. Epub 2015 Sep 4.
Results Reference
result
PubMed Identifier
23179521
Citation
Di Martino M, De Filippis G, De Santis A, Geiger D, Del Monte M, Lombardo CV, Rossi M, Corradini SG, Mennini G, Catalano C. Hepatocellular carcinoma in cirrhotic patients: prospective comparison of US, CT and MR imaging. Eur Radiol. 2013 Apr;23(4):887-96. doi: 10.1007/s00330-012-2691-z. Epub 2012 Nov 18.
Results Reference
result
PubMed Identifier
26280007
Citation
Kudo M, Matsui O, Izumi N, Iijima H, Kadoya M, Imai Y, Okusaka T, Miyayama S, Tsuchiya K, Ueshima K, Hiraoka A, Ikeda M, Ogasawara S, Yamashita T, Minami T, Yamakado K; Liver Cancer Study Group of Japan. JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan. Liver Cancer. 2014 Oct;3(3-4):458-68. doi: 10.1159/000343875.
Results Reference
result
PubMed Identifier
25984845
Citation
Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, Zakher B, Pappas M, Graham E, Sullivan SD. Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 May 19;162(10):697-711. doi: 10.7326/M14-2509. Erratum In: Ann Intern Med. 2015 Jun 16;162(12):880.
Results Reference
result

Learn more about this trial

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

We'll reach out to this number within 24 hrs