Dr. Ming-Ling Chang and Dr. Chung-Guei Huang talk about their experience using PIVKA-II, and their expectations for digital algorithms in HCC surveillance

Interview transcript:

MLC: Ming-Ling Chang

CGH: Chung-Guei Huang

Introduction

MLC: Hi, everyone, I am Dr. Ming-Ling Chang. Currently, I am the Director of the Department of Hepatology and the Gastroenterology of the Chang Gung Memorial Hospital at the Lin-Kou.

CGH: Hello everyone, I am Dr. Chung-Guei Huang. Currently, I am the Director of Department of Medical Laboratory at Lin-Kou Chang Gung Memorial Hospital.

MLC: Chang Gung Memorial Hospital is the biggest chain hospital in
Taiwan with 10 branches and more than 11,000 beds. Chang Gung Memorial Hospital at Lin-Kou is the headquarter among this healthcare system.

CGH: Our laboratory has been CAP accredited since 2003, which means every report from our laboratory meet international standards requirements; we’ve been maintaining CAP accreditation for over 20 years. Beyond CAP accreditation, we also got National Golden Quality Award several times in the past 10 years. Over 1 million tests were reported from our laboratory every month.

What are the challenges in HCC surveillance & diagnosis and testing capacity in your institution?

MLC: In Chang Gung Memorial Hospital, for patients with liver disease, we usually recommend patients with hepatitis to visit our outpatient departments every six months; while those with cirrhosis might have to come every three months. We also conduct liver cancer surveillance by using ultrasound and the alpha fetoprotein, which is AFP. However, not all patients with liver cancer can be diagnosed early despite these measures. The main reason is that the detection rate of tumor by ultrasound is affected by factors such as tumor size, the presence of fatty liver and the liver fibrosis. Moreover, the traditional serum tumor marker AFP only rises in the serum of less than half of the patients with early liver cancer, and can be affected by hepatitis flare leading to false positive results. So, patients with early-stage liver cancer can’t receive timely treatment, and this crucially affects their survival.

CGH: Because of the robust national health insurance system, there are lots of medical behaviors such as blood testing. And the increasing testing loads prompting laboratories to integrate and optimized workflows continuously. Our team had been putting many efforts on streamlining processes for over one decade, making our lab smarter and more efficient, including the application of Artificial Intelligence, business intelligence system, HIMSS 7 close loop system, which helps us successfully release additional testing capacity.

What are the important factors for your lab to consider when selecting a tumor marker?

CGH: As a certificated laboratory, a well-validated assay with official registration approval like CE or FDA is definitely our first priority.

Please share your experience implementing PIVKA-II.

MLC: Currently, in Taiwan, under the National Health Insurance, patients with liver cirrhosis and hepatocellular carcinoma, which is HCC, are entitled to undergo PIVKA-II testing twice a year. This can be complemented with ultrasound and AFP testing. Given the complementary roles of PIVKA-II and AFP in HCC surveillance, their combined use enhances the sensitivity of HCC surveillance, especially for the detection of early-stage HCC. Within hospitals, there have been numerous cases of liver cancer without elevations in AFP levels that were identified through PIVKA-II testing. These patients may exhibit either significant or insignificant ultrasound findings, providing clinicians with greater confidence to proceed with further computer tomography, which is CT, or magnetic resonance imaging, which is MRI, to confirm the diagnosis of liver cancer.

What are your expectations for digital algorithms for HCC surveillance and how is your experience with the new HCC digital algorithm so far?
CGMH is evaluating a new HCC digital algorithm in a clinical study.

MLC: To assess the severity of liver disease, we commonly rely on some algorithms or scores such as fibrosis-4, which is FIB-4, or Child-Pugh score for clinical or decision making. So, there is considerable anticipation for scores like GAAD, which integrates high-risk factors for liver cancer including G for gender, A for age, A for AFP, and the D for DCP, which is PIVKA-II. This integration is expected to serve as an early liver cancer surveillance tool, enhancing efficacy of surveillance, facilitating treatment improvement, and improving patient survival rates. We are still on the road to accumulate the research data on GAAD. If the performance meets expectations, surely, we would like to enroll all patients with high risk for HCC to undergo regular surveillance with GAAD.

CGH: The implementation and calculation framework of GAAD is a brand new trying for laboratories. However, with the rapid development of digitization, AI, and personalized medicine, laboratories are not only dealing with specimens and instruments but also digital algorithms. Facing the trends, laboratories have also strengthened efforts in digital medical talent and ensuring information security.

What advice would you give to other healthcare institutions or professionals looking to improve their HCC management?

MLC: To enhance screening efficacies for early liver cancer in Taiwan, which is a viral hepatitis endemic country, in addition to reinforcing public awareness of liver disease and encouraging regular surveillance among high-risk groups, the surveillance tools should be enhanced. It is important to follow health insurance coverage guidelines when incorporating PIVKA-II. Hopefully, in the future, digital algorithms like GAAD can be applied to further enhance early liver cancer detection rates.

CGH: The values of the testing data offers clinicians as evidence on clinical decisions. In recent years, we focused on the collaboration and communication with clinicians, which contributed to get a better understanding of their perspectives. This allowed us to integrate resources into what clinicians really need and enhancing the value of testing.

What is CGMH’s vision for liver disease and HCC management for the future?

MLC: Hopefully, through collaborative efforts across different units within the healthcare system, the caring for liver diseases, including hepatitis cirrhosis, and HCC, could be enhanced through effective screening, diagnosis, and treatment. In the future, the patients’ quality of life and the survival rates could be improved ultimately.

CGH: Delivering fast and accurate reports is a fundamental requirement for any laboratory. Additionally, we are actively introducing cutting-edge technologies to provide more valuable insights, thereby enhancing early diagnosis rates and patient survival rates.

The views and opinions expressed by Dr. Ming-Ling Chang and Dr. Chung-Guei Huang are their own views and opinions. Roche disclaims all liability in relation to these views and opinions.

Quick Summary

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.

Quick Summary

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).

Quick Summary

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).

Quick Summary

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.

Quick Summary

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

Quick Summary

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

Quick Summary

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

Quick Summary

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.