STOP HCC-GAAD-APAC-Thailand

Official title

A Prospective, Interventional, Longitudinal APAC Study Evaluating Clinical Utility of GAAD Score for Detection of Hepatocellular Carcinoma in a High-risk APAC Patient Population

Overview

Hepatocellular carcinoma (HCC) surveillance is frequently underutilized, and currently available biomarkers, such as alpha-fetoprotein (AFP), demonstrate suboptimal diagnostic performance. This prospective study aims to evaluate a simplified multivariate index, the GAAD score-comprising gender, age, alpha-fetoprotein (AFP), and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-for its ability to improve the detection of hepatocellular carcinoma in patients with chronic liver disease. The study hypothesizes that incorporation of the GAAD score into standard HCC surveillance strategies will improve diagnostic performance compared with existing surveillance modalities alone and may provide evidence to support its inclusion in future clinical practice guidelines.

Detailed description

Surveillance and early detection of hepatocellular carcinoma (HCC) increase the likelihood of potentially curative treatment. However, HCC surveillance remains substantially underutilized, even in countries with adequate healthcare resources. Early-stage HCC can be treated with curative intent using local ablation, surgical resection, or liver transplantation.

The role of serum alpha-fetoprotein (AFP) in HCC surveillance varies across international guidelines. AFP is recommended for surveillance by the Asian Pacific Association for the Study of the Liver (APASL), considered optional by the American Association for the Study of Liver Diseases (AASLD), and not recommended by the European Association for the Study of the Liver (EASL). Similar considerations have informed recommendations for combined use of AFP with ultrasound (US) in HCC surveillance by the World Health Organization (WHO) Guidelines for the Prevention, Care and Treatment of Viral Hepatitis (references 1-4).

AFP has demonstrated suboptimal performance as a serologic surveillance marker for HCC. Serum AFP levels may fluctuate in patients with cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) activity, exacerbations of underlying liver disease, or the development of HCC, thereby limiting its diagnostic accuracy.

Recently, the GALAD score-a multivariable model incorporating gender, age, AFP-L3, AFP, and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-has been proposed as an alternative approach to improve HCC detection and has demonstrated strong diagnostic performance in patients with cirrhotic HCC. A simplified version of this model, the GAAD score (Roche Diagnostics International Ltd., Rotkreuz, Switzerland), which includes gender, age, AFP, and PIVKA-II, has been shown to achieve comparable diagnostic performance in preliminary analyses (Piratvisuth et al., 2023, submitted).

However, the existing evidence supporting the use of the GALAD and GAAD scores is primarily derived from retrospective and/or case-control studies. Prospective validation in real-world surveillance settings remains limited. This study is therefore designed to prospectively evaluate the diagnostic performance of the GAAD score, alone and in combination with standard surveillance modalities, in patients with chronic liver disease undergoing routine HCC surveillance.

Interventions

• Diagnostic test GAAD score
  All enrolled participants will undergo standard hepatocellular carcinoma (HCC) surveillance, consisting of blood sampling and abdominal ultrasound performed every 6 months for a total follow-up period of 24 months. Blood samples will be analyzed for serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) to calculate the GAAD score, a multivariable index incorporating gender, age, AFP, and PIVKA-II. A GAAD score of ≥ 2.57 will trigger a recall procedur

Primary outcome measures

• True Positive Rate (Sensitivity) of Ultrasound, AFP, and GAAD Score as Standalone Surveillance Modalities [Time frame: Over 24 months of patient follow-up]
• False Positive Rate of Ultrasound, AFP, and GAAD Score as Standalone Surveillance Modalities [Time frame: Over 24 months of patient follow-up]
• True Positive Rate (Sensitivity) of Combined Ultrasound + GAAD Score for HCC Surveillance [Time frame: Over 24 months of patient follow-up]
• False Positive Rate of Combined Ultrasound + GAAD Score for HCC Surveillance [Time frame: Over 24 months of patient follow-up]
• True Positive Rate (Sensitivity) of Combined Ultrasound + AFP for HCC Surveillance [Time frame: Over 24 months of patient follow-up]
• False Positive Rate of Combined Ultrasound + AFP for HCC Surveillance [Time frame: Over 24 months of patient follow-up]

Secondary outcome measures (12)

• Area Under the Receiver Operating Characteristic Curve (AUC) of GAAD Compared With Ultrasound, AFP, and PIVKA-II [Time frame: Over 24 months of patient follow-up]
• Sensitivity and Specificity of GAAD Compared With Ultrasound, AFP, and PIVKA-II [Time frame: Over 24 months of patient follow-up]
• Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of GAAD Compared With Ultrasound, AFP, and PIVKA-II [Time frame: Over 24 months of patient follow-up]
• Area Under the Receiver Operating Characteristic Curve (AUC) of Combined Ultrasound + AFP [Time frame: Over 24 months of patient follow-up]
• Sensitivity and Specificity of Combined Ultrasound + AFP [Time frame: Over 24 months of patient follow-up]
• Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of Combined Ultrasound + AFP [Time frame: Over 24 months of patient follow-up]
• Longitudinal Changes in AFP Levels Prior to HCC Diagnosis [Time frame: Over 24 months of patient follow-up]
• Longitudinal Changes in PIVKA-II Levels Prior to HCC Diagnosis [Time frame: Over 24 months of patient follow-up]
• Longitudinal Changes in GAAD Score Prior to HCC Diagnosis [Time frame: Over 24 months of patient follow-up]
• Number of Additional Early-Stage HCCs Detected Using GAAD [Time frame: Over 24 months of patient follow-up]
• Number of Additional CT or MRI Imaging Procedures Triggered by Surveillance Tests [Time frame: Over 24 months of patient follow-up]
• Relative False Positive Rate of Additional CT or MRI Imaging Procedures [Time frame: Over 24 months of patient follow-up]

Eligibility criteria

Inclusion criteria

• Adults with chronic liver disease who have an indication for hepatocellular carcinoma (HCC) surveillance, including one or more of the following:
• Liver cirrhosis of any etiology (e.g., chronic hepatitis B virus \[HBV\], chronic hepatitis C virus \[HCV\], metabolic dysfunction-associated steatohepatitis \[MASH\], or alcohol-related liver disease \[ALD\])
• Non-cirrhotic chronic liver disease (e.g., HCV, MASH, or ALD) with evidence of stage F3 fibrosis
• Chronic HBV infection with a clinical diagnosis of non-cirrhotic liver disease

Exclusion criteria

• Diagnosis of any active malignancy other than non-melanoma skin cancer
• History of previously diagnosed malignancy, including prior hepatocellular carcinoma
• Life expectancy of less than 2 years
• Use of vitamin K antagonists within 1 week prior to enrollment
• Pregnant or breastfeeding women
• Estimated glomerular filtration rate (GFR) < 60 mL/min/1.73 m²
• Significant hepatic decompensation or Child-Pugh class C liver disease
• Unwillingness or inability to undergo computed tomography (CT) or magnetic resonance imaging (MRI)
• Unwillingness or inability to provide informed consent or to participate in the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Screening

Study locations

Thailand · 1 center

• Faculty of Medicine Siriraj Hospital — Bangkoknoi

Publications

• Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, Waljee AK, Singal AG. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology. 2018 May;154(6):1706-1718.e1. doi: 10.1053/j.gastro.2018.01.064. Epub 2018 Feb 6. PMID 29425931
• Best J, Bechmann LP, Sowa JP, Sydor S, Dechene A, Pflanz K, Bedreli S, Schotten C, Geier A, Berg T, Fischer J, Vogel A, Bantel H, Weinmann A, Schattenberg JM, Huber Y, Wege H, von Felden J, Schulze K, Bettinger D, Thimme R, Sinner F, Schutte K, Weiss KH, Toyoda H, Yasuda S, Kumada T, Berhane S, Wichert M, Heider D, Gerken G, Johnson P, Canbay A. GALAD Score Detects Early Hepatocellular Carcinoma i PMID 31712073
• Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul;11(4):317-370. doi: 10.1007/s12072-017-9799-9. Epub 2017 Jun 15. PMID 28620797
• European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019. Epub 2018 Apr 5. No abstract available. PMID 29628281
• Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023 Dec 1;78(6):1922-1965. doi: 10.1097/HEP.0000000000000466. Epub 2023 May 22. No abstract available. PMID 37199193

Identifiers

NCT: NCT07319299 · Si 089/2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗