Quick Summary

The incidence of AFP-negative HCC is increasing worldwide, particularly HCCs of nonviral etiology, such as MASLD/MASH. A high percentage of patients with MASLD/MASH-related HCC are positive for PIVKA-II, even those who are negative for AFP[1]. Higher levels of AFP-L3 have also been reported in cases of MASLD/MASH-related HCC [2]. Thus, the role of PIVKA-II and AFP-L3 measurements in HCC surveillance and diagnosis of AFP-negative HCCs has become more important.
This article by Prof Masatoshi Kudo details the importance of testing all 3 biomarkers, AFP, AFP-L3, and PIVKA-II, in HCC surveillance and management. He also discusses new algorithms, such as GALAD and GAAD, which incorporate these biomarkers have been useful in countries where access to imaging is limited.

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The risk of hepatocellular carcinoma (HCC) is reduced but not eliminated after nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB). This study aimed to investigate the role of serum Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) and alpha-fetoprotein in predicting HCC and mortality in cirrhotic CHB patients at virological remission (VR) following NA therapy. 

 

Patients with CHB-related cirrhosis undergoing NA therapy from two medical centers in Taiwan were retrospectively included. Serum PIVKA-II were quantified by an automated chemiluminescence assay. Multivariable Cox proportional hazards regression models were used to identify predictors for HCC and death. Serial on-treatment PIVKA-II levels after VR were investigated.

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Serum biomarkers are valuable for clinical decision-making for patients with hepatocellular carcinoma (HCC), among which the most promising are AFP, AFP-L3, DCP, DKK-1, and GP73; however, the efficacy of using combined biomarkers remains controversial. This meta-analysis provides insights regarding this topic.

 

PubMed, Embase, and Cochrane Library were systematically surveyed, and 28 qualified articles published since January 2015 were identified. A random-effects model was used to assess pooled sensitivity, specificity, positive and negative likelihood ratios (PLRs and NLPs), and diagnostic odds ratio (DOR).

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Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and the mortality rate remains high. More than 70% of HCC patients have recurrence within 5 years after treatment. The purpose of this study is to evaluate the prognostic values of serum markers with retrospective data.

 

Real‐world data (RWD) was applied to analyze the prognostic values of six serum markers for HCC patients after treatment, including α‐fetoprotein (AFP), α‐fetoprotein‐L3 (AFP‐L3), Golgi protein73 (GP73), alanine aminotransferase (ALT), albumin (ALB), and total bilirubin (TBil). A total of 268 cases were enrolled to analyze recurrence‐free survival (RFS), and 104 cases were used to analyze overall survival (OS).

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At present, the diagnostic accuracy of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is insufficient. It remains controversial whether prothrombin induced by vitamin K absence II (PIVKA-II) has a better diagnostic value than AFP for HCC patients.This study aims to investigate the diagnostic role of PIVKA-II alone or in combination with AFP in Chinese HCC patients.

 

Serum AFP and PIVKA-II levels were detected and analyzed in 308 HCC afflicted patients and 120 unafflicted controls. The receiver operator curve (ROC) and area under the curve (AUC) were conducted to evaluate the clinical value of AFP and PIVKA-II for diagnosing HCC and early HCC.

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The aim of this study was to investigate the efficacy of combined detection of 5 serological tumor markers including macrophage migration inhibitory factor (MIF) and abnormal prothrombin (PIVKA-II) in the early diagnosis of primary liver cancer.

 

A total of 90 patients with suspected primary liver cancer admitted from January 2016 to May 2017 were selected as the research subjects. All patients were examined by imaging and histopathology. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum MIF, GP73 and PIVKA-II. Automatic electrochemiluminescence immunoassay system was used to detect serum AFP and AFP-L3. The diagnostic value of single and combined detection of five serological tumor markers for primary liver cancer was compared and analyzed.

Quick Summary

Despite moderate sensitivity, alpha fetoprotein (AFP) is widely used in screening and prognostication for hepatocellular carcinoma (HCC). The objective of the current study was to assess clinical utility of Prothrombin induced by Vitamin K absence-II (PIVKA-II) in addition to AFP in patients with HCC.

 

244 patients with documented AFP, PIVKA-II and dynamic imaging of the liver were reviewed retrospectively. Using ROC curves, cutoff values for AFP and PIVKA-II for HCC detection, tumor grade and microvascular invasion (MVI) were assessed. In patients who underwent liver transplantation (LT) for HCC, survival was determined using Kaplan Meier curves.

Meta-analysis to evaluate the performance & diagnostic value of AFP and PIVKA-II across different HCC risk factors

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This meta-analysis aimed to clarify the diagnostic value of these two serum markers in patients with different risk of HCC development, such as etiology, ethnicity, and various stages of tumor. The impact of varying study types of literature and detection methods of index test on the diagnosis outcome was also explored, providing evidence for the two serum markers in the clinical management of patients at risk of tumor development.

The authors found that overall, the diagnostic accuracy of DCP (PIVKA-II) was superior to AFP. However, the diagnostic performance of AFP and DCP (PIVKA-II) was different in different ethnicity, etiology, and detection methods. The authors concluded that the combination of DCP (PIVKA-II) and AFP can improve the effectiveness of surveillance for patients at risk of HCC.

Meta-analysis of biomarkers for HCC diagnosis, including AFP, DCP (PIVKA-II), GPC3, GP73, Hsp90alpha, midkine, and OPN

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Hepatocellular carcinoma lacks ideal diagnostic biomarkers. There is a lack of scientific evaluation of relevant promising biomarkers as well. Therefore this study reanalyzes the related studies of 11 blood biomarkers of HCC, and compares the diagnostic value of these biomarkers for HCC systematically.

The authors found that the combination of AFP and other biomarkers improved the diagnostic efficiency. The diagnostic value of biomarkers including DCP (PIVKA-II), GPC3, GP73, Hsp90alpha, midkine, and OPN was higher than that of AFP. GP73 had the best diagnostic value for HCC.

Performance review of Phase II liver cancer tumor markers & biomarker panels for the early detection of HCC

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the cancer with the fastest increase in mortality in the United States, with more than 39,000 cases and 29,000 deaths in 2018. As with many cancers, survival is significantly improved by early detection. The median survival of patients with early HCC is >60 months but <15 months when detected at an advanced stage. Surveillance of at-risk patients improves outcome, but fewer than 20% of those at risk for HCC receive surveillance, and current surveillance strategies have limited sensitivity and specificity.

Ideally, blood-based biomarkers with adequate sensitivity or specificity would be available for early detection of HCC; however, the most commonly used biomarker for HCC, alpha-fetoprotein (AFP), has inadequate performance characteristics. There are several candidate serum proteomic, glycomic, and genetic markers that have gone through early stages of biomarker validation and have shown promise for the early detection of HCC, but these markers require validation in well-curated cohorts. Ongoing prospective cohort studies will permit retrospective longitudinal (phase III biomarker study) validation of biomarkers. In this review, the authors highlight promising candidate biomarkers and biomarker panels that have completed phase II evaluation but require further validation prior to clinical use.