Every year, liver cancer claims 740,000 lives worldwide, with 42% of these deaths occurring in China. In China, the 5-year survival for hepatocellular carcinoma (HCC) patients is just 14.4%, and over 80% of liver cancer patients diagnosed are those with Hepatitis B. Despite this alarming statistic, early screening and comprehensive, end-to-end disease management approaches remained limited in China. This created a critical gap in care, one that Zhuhai People’s Hospital in collaboration with Roche, aimed to address with the initiation of Project Pearl in 2022.

Project Pearl is a pioneering multi-stakeholder initiative designed to provide holistic care to patients with chronic liver disease by enabling end-to-end chronic disease management involving healthcare professionals, hospital administration, and payors. At its core, the project leverages on the Liver Integrated Solution, comprising of two key digital solutions:

• Liver Disease Pathway (LDP), a digital platform streamlining HCC screening workflow and offering a patient portal for better care management
• Oncology Hub (OH), a clinical workflow for multidisciplinary team meetings and decision support system

This integrated solution empowers clinicians with the right information at the right time, ensuring informed, precise decision-making throughout the patient’s journey.

Let’s explore how the patient’s journey has evolved under this new framework. Upon their first hospital visit, patients with chronic liver disease are registered on the digital solution, and are evaluated with abdominal ultrasound, AFP, PIVKA-II, and GAAD, aimed at early detection of HCC. The patients’ data and reports are synchronized for physicians to view in real time. Meanwhile, risk stratification scores provide physicians with a clearer understanding of each patient’s likelihood of developing liver cancer, allowing for more personalized, periodic surveillance plans. Physicians are able to easily arrange follow-ups with the patients and track their disease progression over time. Beyond the hospital, an interoperable mobile platform extends support with follow-up reminders, report interpretation, patient education, and 1 on 1 consultation. This empowers patients to better understand their condition and also ensures they receive continuous, standardized care, essential for early detection and intervention. For physicians, the new patient journey not only streamlines operations but also enhances clinical effectiveness by enabling early detection, offering curative treatment options, and improving patient outcomes.

The entire clinical and operational workflow from screening and diagnosis and follow-up is now automated, making it easier to manage every step of care delivery. Once patients are diagnosed with HCC, they are seamlessly transitioned into a comprehensive treatment management system. This integrated approach addresses the following challenges that are commonly observed in MDT care delivery. Lack of standardized MDT clinical protocol, absence of robust post-treatment follow-up system, and limited capabilities to analyse and gain insights from treatment data. Upon transition, a patient’s 360 report is automatically generated to show their entire patient history. This empowers them with data-driven insights to deliver clinical, operational and economic outcomes to manage HCC treatment more effectively and confidently.

Ultimately, Project Pearl enables a win for all stakeholders. For patients, early detection and personalized care plans lead to better outcomes. For physicians, streamlines, standardized workflows and digitally-enabled decision-making support clinical practice in a timely and effective manner. For the health system, the project accelerates the goals of “Healthy China 2030”, improving outcomes at reduced costs. By improving both patient outcomes and healthcare efficiency, we are taking significant steps toward a future where liver cancer can be detected early and treated effectively, creating hope for thousands of lives.

Since its launch, Project Pearl has seem promising results. Till date, 4,972 patients had been screened, and 40 cases of HCC had been diagnosed. Remarkably, 39 of those cases were detected at an early stage, offering significantly better chances for curative treatment. These outcomes demonstrate the project’s real-world impact in transforming liver cancer care and improving patient outcomes.

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 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.

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.

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.