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

Hepatocellular Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04414956
• Other study ID #: HCCAFPL3
• Status: Recruiting
• Phase: N/A
• Start date: July 1, 2016
• Est. completion date: February 28, 2026

Study information

• Verified date: May 2020
• Source: Korea University
• Contact: Hyung Joon Yim, MD,PhD
• Phone: +82-31-412-6565
• Email: gudwns21[@]korea.ac.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1418
• Est. completion date: February 28, 2026
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Fibrosis
• Hepatocellular Carcinoma
• Liver Cirrhosis
• Surveillance

Intervention

Diagnostic Test:
• AFP-L3
AFP-L3 will be tested using serum sample every 6 months.
• AFP
AFP will be tested using serum sample every 6 months.
• PIVKA-II
PIVKA-II will be tested using serum sample every 6 months.
• Sonography
Sonography will be tested by experts every 6 months.
• CT
Contrast-enhanced CT will be tested annually.

Locations

Country	Name	City	State
Korea, Republic of	Korea University Ansan Hospital	Ansan	Gyeonggi-do
Korea, Republic of	Keimyung University Dongsan Medical Center	Daegu
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung-Ang University Hosptial	Seoul
Korea, Republic of	Hanyang University Hospital	Seoul
Korea, Republic of	Inje University SangGye Paik Hospital	Seoul
Korea, Republic of	Konkuk University Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	Soonchunhyang University Seoul Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St.Mary's Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Uijeongbu St.Mary's Hospital	Uijeongbu	Gyeonggi-do

Sponsors (15)

Lead Sponsor

Collaborator

Korea University

Asan Medical Center, Chung-Ang University Hosptial, Chung-Ang University College of Medicine, Hanyang University, Inje University, Keimyung University Dongsan Medical Center, Konkuk University Hospital, Korea University Anam Hospital, Korea University Guro Hospital, Korea Unversity Ansan Hospital, Samsung Medical Center, Seoul National University Hospital, Severance Hospital, Soonchunhyang University Hospital, The Catholic University of Korea

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (17)

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. — View 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: 1 — View 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. — View Citation

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011 Sep 22;365(12):1118-27. doi: 10.1056/NEJMra1001683. Review. — View 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. Erratum in: J Hepatol. 2012 Jun;56(6):1430. — View 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. — View 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 fo — View 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; — View 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 accord — View 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 L — View 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 — View 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 h — View 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) — View 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. — View 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. Review. — View 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 — View 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 — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HCC occurrence	Detection of HCC occurrence by three biomarkers and two image modalities	3 years after enrollment
Secondary	Early HCC occurrence	Detection of HCC less than 2cm	3 years after enrollment