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.

Prof Tawesak Tanwandee and Asst Prof Sansnee Senawong demonstrates how digital algorithms are used in Siriraj Hospital for the early detection of HCC

Interview transcript:

TT: Prof. Tawesak Tanwandee

SS: Asst. Prof. Sansnee Senawong

Introduction

TT: My name is Tawesak Tanwandee, Professor of Medicine, Head of Division of Gastroenterology, Faculty of Medicine, Siriraj Hospital.

SS: Hello, I am the Assistant Professor of Medicine, Sansanee Senawong, Chief of the Immunology Department, Faculty of Medicine, Siriraj Hospital, Mahidol University.

TT: Siriraj Hospital is the largest and the oldest hospital in Thailand. As it is a large and highly advanced hospital, a large number of patients come to Siriraj Hospital annually.

SS: The laboratory of the Department of Immunology was certified by the international standard ISO 15189 since May 2006. It has passed the continuous evaluation and inspection for the ISO 15189:2012 standards to date.

TT: As we are a large hospital, we receive patients from other hospitals. The patients who are referred to our hospital are mostly terminally ill. They are already in the terminal stage of cancer.

What is the unmet need in HCC surveillance and diagnosis in Siriraj Hospital?

SS: In Thailand, liver cancer is one of the most common and leading causes of death in cancer patients in the country. We find that over 70% of patients who die of liver cancer are not admitted to the surveillance program, resulting in delayed diagnosis at the terminal stage and they pass away soon after.

TT: For patients at risk of liver cancer, we don’t always have the chance to screen them sufficiently at an early stage. Moreover, an early stage of liver cancer has no visible symptoms. Therefore, the patient does not realize they need to be tested.

SS: In terms of liver cancer, there are still challenges regarding the effectiveness of liver cancer surveillance.

TT: The standard practice for liver cancer surveillance today is composed of ultrasound scans and blood (biomarker) tests to check alpha fetoprotein (AFP) levels every 6 months.

SS: However, we find that the sensitivity rate is as low as 63%.

TT: Due to ultrasound capacity limitations, patients may have to wait for months or even a year for a scan. Ultrasound also relies heavily on the doctor conducting the scan and how meticulous they are. Patients who are obese or have been diagnosed with liver cirrhosis, may be difficult to detect liver cancer by ultrasound.

SS: As a laboratory, when choosing a test or a platform for our services, we must take into account the challenge of reporting laboratory results quickly and efficiently to keep up with the increasing laboratory workloads. Also, it has to minimize human errors as much as possible. We need to find an appropriate system that can support various biomarker testing and is reliable.

What is your clinical experience with PIVKA-II? How has it brought value to HCC diagnosis?

TT: The data from studies show that PIVKA-II was quicker to detect early stages of liver cancer in patients. Checking the levels of AFP and PIVKA-II at the same time is much more convenient to doctors. Therefore, a single blood test from the patient allows both tests to be run. When testing both, we see for some patients, that the level of AFP is normal but the PIVKA-II level is abnormal. This helps to alert the doctor to abnormalities in the patient.

SS: Providing PIVKA-II to use in our laboratory will help improve the efficiency of early liver cancer surveillance in the future.

What is your experience using digital algorithms? How does the digital algorithm bring value to enable early HCC diagnosis?

TT: There are about 50-60 patients who have used the digital algorithm. And it has been very beneficial to some patients.

SS: But due to the limitations of ultrasound access combined with the sensitivity performance of AFP, considering to add new biomarkers such as PIVKA-II and  the digital algorithm will play a very important role.

TT: When applying the digital algorithm, in practice, we have to add two other factors, age and gender. Sometimes, abnormalities in the AFP level or PIVKA-II level is detected. But the digital algorithm shows it as normal. The algorithm makes surveillance more accurate.

SS: According to many studies and the reports from the doctors who directly treat the patients, it was found that using PIVKA-II and the digital algorithm, compared to the results of AFP and ultrasound, which is considered standard/conventional practice, helps detect liver cancer at an early stage more efficiently.

What does your workflow using the digital algorithm look like?

TT: The digital algorithm has simplified the workflow. Every time a patient has a health check, it’s standard practice to run a blood test to check the liver health. With the blood sample, we can run the digital algorithm at the same time. This means the patient only needs to give one blood sample. Everything is done in one visit.

SS: After collecting the samples, the laboratory performs AFP, PIVKA-II, and digital algorithm tests. After the AFP and PIVKA-II test results are reported, the laboratory results will be combined with gender and age to automatically calculate the score. The result will be sent to the LIS or HIS system of the hospital, allowing the doctors to see the test results quickly. This makes the laboratory workflow more convenient and reporting of results faster.

TT: It’s very easy to interpret the result because there is only ‘positive’ or ‘negative’ (score). The doctors don’t need to interpret complicated numbers. When an abnormality in the digital algorithm is found, the doctor should conduct further (confirmatory) testing, especially using medical imaging techniques such as X-ray, CT or MRI scans.

What’s your expectation for the digital algorithm in the future?

TT: If we use the digital algorithm or PIVKA-II in addition to AFP, the liver cancer surveillance will likely be more accurate because this test already shares the same platform as their regular blood tests. And this will help us to decide if the patient is at risk of cancer, or need further surveillance tests. We might be able to detect the liver cancer at an earlier stage in more patients and provide successful treatment.

What is Siriraj  Hospital’s vision for the liver disease and HCC management?

TT: In patients who have been screened and found to have liver cancer, over 90% of them live longer than 5 years. In this case, it changes the patient’s life. If we can use other surveillance methods such as PIVKA-II or the digital algorithm, it might help to improve surveillance effectiveness.

SS: The department is very pleased to have been a part of an important step in using digital diagnostic tools which are helping liver cancer patients have a better quality of life and increase the survival rate.

TT: At Siriraj Hospital, we provide knowledge and raise awareness for everyone, which includes both patients and healthcare workers. So, the patients who are at risk of liver cancer, can receive surveillance regularly. We hope that in the future, every patient who is at risk of liver cancer, everyone in Siriraj Hospital, will receive the surveillance process regularly.

The views and opinions expressed by Prof. Tawesak Tanwandee and Asst. Prof. Sansnee Senawong are their own views and opinions. Roche disclaims all liability in relation to these views and opinions.

Prof MF Yuen & Ronald Lo discuss the liver health ecosystem in Hong Kong, including hepatitis screening and HCC surveillance

Find out more about PIVKA-II in Hepatocellular Carcinoma (HCC) detection, or download our HCC Detection (HD) expert pack by filling in the form below:

Interview transcript:

Ronald Lo:

Hello everyone! Welcome to this video. I’m Ronald, the General Manager of Roche Diagnostics Hong Kong. It’s my honour today to invite Professor Yuen to have a discussion around the topics of hepatitis and hepatocellular carcinoma (HCC). Hello Professor Yuen.

Prof. MF Yuen:

Hi, I am Professor MF Yuen, the Chief of Division of Gastroenterology and Hepatology in the University of Hong Kong.

Ronald Lo:

Again, thank you so much for joining us today. So the first question I would like to get your advice would be, what is the current liver health landscape in Hong Kong; and what are the unmet needs in hepatitis screening and HCC detection in Hong Kong?

Prof. MF Yuen:

At present, Hong Kong still has a high prevalence of 7.8% hepatitis B population, amounting more than 550,000 people. According to the most recent statistics, there were more than 1,700 new cases of liver cancer in 2020. And it is known that more than 80% of Hepatocellular Carcinoma are caused by Hepatitis B infection. Even with this high rate, we do not have population screening program for Hepatitis B infection, and the surveillance for HCC is also suboptimal with respect to the lack of routine regular ultrasound of the liver for Hepatitis B patients. It is mainly due to manpower and financial constraint in the public hospital sector. On top of all these, we do not have a well-organised strategy to deliver disease information to our population. Majority of people do not know the serious disease consequence of Hepatitis B infection which may lead to early death. They also lack of knowledge of early treatment would prevent all these deleterious outcomes.

Ronald Lo:

So I would like to learn from you more, what are the recent advances in the diagnosis of HCC; and how do you see these impacting patient care and the chronic liver disease management in Hong Kong?

Prof. MF Yuen:

From Asian experience, the use of additional biomarkers, such as PIVKA-II, can significantly increase the pick-up rate of HCC at early stage, increase the likelihood for curative treatments, and thus improve the survival. New digital algorithms combining age, gender and biomarkers, such as GAAD and GALAD, have been proposed since 2013, and currently undergoing clinical validations. Recent data presented during APASL 2023 demonstrated that the use of PIVKA-II based algorithm is more cost-effective than current standard of care among Hepatitis B or cirrhotic patients in Hong Kong, which allows an earlier HCC detection and a reduced cost in subsequent HCC treatment.

Ronald Lo:

Let’s switch the gear a bit. So how do you think we can improve the coordination and integration of care among various healthcare providers and systems?

Prof. MF Yuen:

I think the most important step would be the active involvement of different concerned parties, including health care sectors from government, private institutions, policy makers, patient groups, and different NGOs, to establish a core committee which could liaise with different stakeholders to ensure the implementation of different measures to enhance diagnosis rate, screening strategy and treatment.

Ronald Lo:

And to add on, how do you see the future of liver health in Hong Kong, and what steps do you believe need to be taken to improve the patient outcomes?

Prof. MF Yuen:

The future of liver health in Hong Kong depends on whether we could have a statutory body which taking charge of planning, liaising and implementing different measures at different levels.

Ronald Lo:

Thank you Professor. So probably would be my last question. So how do you see the role of the government and the policy in addressing the liver health ecosystem?

Prof. MF Yuen:

Hong Kong government has been working on different policy making processes and decisions by involving different committees. However, the decisiveness should be more enhanced so that policy can be rolled out at a timely manner.

Ronald Lo:

Professor Yuen, thank you so much for your time today and your inspiring insights on the topics of hepatitis and HCC. And I’m sure that there are always many areas that we could further work on together to improve patient outcomes. And thanks a lot for contributing to the “Combating Cancer” educational platform as well. Thank you so much, thank you!

The views and opinions expressed by Prof. MF Yuen are his own views and opinions. Roche disclaims all liability in relation to these views and opinions.

Interviews with APAC liver disease
experts reveal 7 priorities for implementing HCC surveillance programs

Quick Summary

HCC is a leading cause of cancer mortality in Asia. Causes of HCC include viral hepatitis B and C infections, with recent increases in metabolic disorders, such as NAFLD, also playing a factor.

Early HCC interventions are highly effective and can lead to improved patient outcomes and survival. Therefore, HCC surveillance programs are pivotal in detecting HCC early and making the appropriate interventions.

In this whitepaper, HCC surveillance programs in Asia were analysed. The learnings from well established HCC surveillance programs in Asia, as well as the challenges in areas that have not implemented such programs have highlighted 7 priorities for implementing an HCC surveillance program:

Include HCC surveillance in national program and strategic plans

HCC surveillance programs should be fit into the national health strategy where appropriate, taking into account the local incidence and prevelance rates, and existing priorities and resources.

Secure sustainable funding commitments

Long-term resourcing and financing is key to making HCC survaillance programs successful. The current health financign system in the area, and ability to pay should be assessed, while exploring various funding methods such as centralised healthcare coverage or private insurance.

Collect, analyse, and utilise data to inform program design

The development of HCC surveillance program should be based on data, such as HCC epidemiology, patient outcomes, human and economic cost of HCC. These data should be collected and analysed.

Adopt optimal technologies to advance HCC surveillance

Technology can help to improve access to HCC surveillance programs, as well as improve patient outcomes by detecting HCC early. Some examples include: including additional biomarkers such as PIVKA-II, using biomarker based digital algorithms and diagnostic models, using more advanced imaging techniques, and adapting IT systems to support surveillance programs.

Mobilise existing resources for HCC surveillance

Tapping on exisiting resources to expand capacity for HCC care and surveillance., For example increasing the range of HCPs who can diagnose and manage HCC like primary and community HCPs, expanding private healthcare capacity in HCC care.

Engage a broad spectrum of stakeholders to further surveillance goals

Governmental decision-makers, physicians, patients and PAGs, payers and industry need to come together to drive implementation of a robust HCC surveillance programs that address needs of all stakeholders.

Raise awareness and provide education on the need for HCC suveillance

Raising the knowledge among the general population and HCPs on HCC and the importance of surveillance can improve uptake and compliance to surveillance programs.

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

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul.

The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.

Quick Summary

Most published guidelines for genomic biomarker testing in NSCLC reflect the disease epidemiology and treatments readily available in Europe and North America. Nevertheless, 60% of annual global NSCLC cases occur in Asia, where patient characteristics, tumor molecular profiles, and treatments vary greatly from the Western world. For example, mutations in the EGFR occur at a higher prevalence in Asia than in other world regions. Although medical associations such as the International Association for the Study of Lung Cancer, European Society for Medical Oncology, and American Society of Clinical Oncology have described principles for tumor genomic biomarker testing in NSCLC, there is a need for recommendations specific for Asia.

This report provides consensus recommendations for NSCLC biomarker testing from Asian lung cancer experts for clinicians working in Asia to improve patient care. Biomarker testing approaches for actionable genetic alterations in EGFR, ALK, ROS1, and others are discussed for nonmetastatic and metastatic forms of adenocarcinoma and squamous cell carcinoma.

What are the greatest challenges in the early detection of Hepatocellular Carcinoma (HCC)?

So, what are the greatest challenges in the early detection of HCC? I would say, it’s firstly identifying the patients who are at risk for HCC; and in the large, that’s the patients with cirrhosis, and at the moment we’re not detecting those patients with cirrhosis, who are the greatest population at risk. So, what do we need to do about that? Well, we need to find them; and that means empowering the GPs, particularly, to have early detection of cirrhosis, so they can enroll patients in surveillance for HCC.

What is one thing you would do to improve HCC surveillance?

If I was to improve one thing in HCC surveillance, what would that be? Well again, I think it’s that first step in identifying the patients who need surveillance. But then once you’ve done that, how do you get most patients to surveillance? Well in the Australian context, that’s going to mean having a test that’s affordable, and that’s effective, and that is applicable to patients wherever they are in Australia. So it might be that one sort of test is available to somebody who lives very close to a major tertiary hospital, but for many many people in Australia, they’re not in that situation. They’re going to be living in rural or remote Australia, in regional towns, all over the country; because the risks of liver disease are diverse, and we’ve got to have a surveillance test that is applicable to all of them.

What are the challenges for patients in maintaining HCC surveillance? How can we overcome these?

So these are patients who we know they should be having surveillance. The patients know they should be having surveillance, and their doctors know they should be having surveillance, and there are challenges yet to getting those patients in regular surveillance. And by surveillance, we mean an assessment that’s conducted every 6 months, and currently that would be an ultrasound with or without an AFP level. So the challenges those patients have is firstly, they forget, their doctors forget, they drop out of follow up. The COVID pandemic had a huge impact in people being reluctant to access care and to go to diagnostic centers for imaging, for blood tests even. And then there are patients that move. There are patients that have to pay out of pocket to access testing, so the financial barrier is huge, and particularly the community of patients who live with liver disease are often the patients who can’t afford to access non-Medicare funded investigations. So having tests that are affordable, accessible, near them that they remember to have with regular reminders, are all ways that we can overcome those challenges.

What is the optimal model of care in HCC surveillance?

So what is an optimal model of care for an HCC surveillance program? Well it might be that there is not one model for everybody; and if people are coming regularly to a major center or have access to high quality ultrasound and blood testing, then a combination of ultrasound and blood testing might be what’s suitable for them. For other patients, another model of care might be more appropriate where they don’t have regular access to ultrasound, but where a blood test that had high sensitivity and high specificity may fill that gap. So it’s going to be varied, it’s going to be dependent on what the access to medical care is, what the access to imaging and blood testing care is, what the access to, perhaps, nursing care is; dependent on where that patient is, and where they live in the country.

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.