Redefining HCC Surveillance in India: A Call for Innovative and Inclusive Strategies

Abstract

Hepatocellular carcinoma (HCC) is one of the top ten leading causes of cancer-related death in India, with recent reports suggesting a rising incidence. Chronic HBV infection is still the commonest cause of HCC in India but the recent surge of MASLD and better control of viral hepatitis is already changing the epidemiology. Most HCC in India are diagnosed at an advanced stage where cure is impossible, and prognosis is poor. These factors force us to rethink strategies for surveillance and diagnosis of early stage HCC in India.

Current guidelines including from INASL, suggest six-monthly surveillance using abdominal ultrasound (USG) with or without Alpha Fetoprotein (AFP) testing. This strategy has several limitations, especially in patients with MASLD. Also, HCC surveillance is neither well-organized nor universally practiced in India. The current screening approach, therefore needs a radical change. The Japanese guidelines provide a template for a successful model for increasing the diagnosis of early HCC. Tumor markers like PIVKA II, and newer algorithms like the GALAD and the GAAD scores could refine the surveillance strategies in the coming years, as shown by emerging data from Thailand and China. Moving away from hospital-based imaging towards community-based use of blood markers and digital technology may be a potential solution to help reach at-risk populations.

Healthcare economics and logistics will play a big part in implementation of a radical new strategy, and a nationwide chronic liver disease and HCC registry is needed to evaluate current practices, define populations at risk, and identify the best beneficiaries of surveillance in a resource-constrained setting like India. We also concurrently need to identify, upgrade or develop statewide centers of excellence to provide state-of-the-art integrated multidisciplinary care to patients who get diagnosed through surveillance pathways to actually improve patient outcomes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide.¹ Most cases of HCC are diagnosed in an advanced stage where curative treatment is no longer possible and overall survival is dismal, healthcare costs are high, and quality of life is adversely affected. The poor prognosis associated with HCC in most regions of the world can be attributed to delayed diagnosis due to inadequate use of HCC surveillance in patients with cirrhosis.²

HCC surveillance with 6 monthly abdominal ultrasonography (USG) with or without tumor markers is associated with early tumor detection, curative treatment, and improved outcomes.³ The number of patients with cirrhosis who undergo regular surveillance is abysmally low due to multiple challenges at different levels in health care delivery systems. This number is expected to be even lower amongst patients residing in rural and underserved areas and in patients with low socioeconomic status, contributing to disparities in HCC outcomes between various centers and regions.⁴

The need of the hour is a radical change in the current surveillance strategies with an India-specific outlook to improve diagnosis of early HCC. Setting up a special interest group with evaluation of existing surveillance practices and targeting the identified deficiencies should be the first step followed by research on predictive models and cost effectiveness in the Indian scenario and efforts for capacity building.

In this review article, we discuss the changing epidemiology of HCC, the rationale and recommendations for surveillance, challenges to surveillance and strategies to overcome these challenges, and outline a path ahead.

Epidemiology of HCC in India

Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020 as per GLOBOCAN estimates.¹ Hepatocellular cancer is the commonest primary liver cancer and has a geographical variation in incidence. The risk factors vary with region. The commonest risk factor worldwide is viral hepatitis B or C with almost 60% of HCC being potentially attributable to either Hepatitis B virus (HBV) or Hepatitis C virus (HCV) in most countries.⁵

HBV infection with or without Aflatoxin exposure is the commonest risk factor in high incidence areas like China and sub-Saharan Africa while HCV is the commonest risk factor in some developed countries like Japan. There are many factors like age, ethnicity, viral load, co-infection with HCV etc. that modify the HCC risk in individuals with chronic HBV infection. Similarly, factors like male sex, genotype, co-infection with HBV or human immunodeficiency virus (HIV), obesity etc. modify the HCC risk in individuals with chronic HCV infection.⁶ Most HCC occur in the setting of cirrhosis.

Global trends reveal increasing incidence of HCC in North American and European countries and decreasing or stable rates in Asian countries.⁷ The decreasing incidence has been largely due to the effect of HBV vaccination leading to a decreasing burden of HBV and also, improved treatment of HCV infection with direct acting antivirals (DAA).

With the increasing incidence of obesity, type 2 diabetes mellitus and metabolic syndrome, Non-alcoholic fatty liver disease (NAFLD), [now renamed as metabolic dysfunction-associated steatotic liver disease (MASLD)] is increasingly becoming a common risk factor for a different type of HCC with unique characteristics, including being equally prevalent in both genders and possibly associated with suboptimal response to immunotherapy.⁸

HCC is an uncommon cancer in India with age standardized rates of 3.9 per 100,000 for males and 1.6 per 100,000 population for females accounting for 3.8% of the HCC cases worldwide.^9,10 It is the 11th commonest cancer and 8th common cause of cancer related deaths in India.⁹ A study evaluating the National Cancer Registry Program (NCRP) data reported a rising trend of liver cancers in India over almost three decades.¹¹

Indian literature on HCC is heterogeneous, but data from the larger single-center studies reveal that Chronic HBV infection is still the commonest etiology of HCC reported from India.^12,13 A few studies from south India have reported contrasting findings with a higher proportion of HCC patients having alcohol-related related liver disease (ALD) or MASLD as the predominant etiology.^14,15 However, most recent studies from India even from centers with predominant HBV related etiology have reported a significant number of MASLD related HCC. A recent large multi-centre study from India reported that NAFLD was the commonest risk factor in 35.5% followed by viral hepatitis B and C and ALD and that 27.9% HCC did not have cirrhosis.¹⁶ A systematic review and meta-analysis published recently concluded that viral hepatitis (HBV infection) is still the commonest etiology of HCC in India. NAFLD related HCC is on the rise with a concurrent decrease in HBV related cases.¹⁷

Most large studies on HCC from India report a significant number of patients presenting in an advanced stage at diagnosis where no curative treatment is possible and treatment options are limited.^12,13 This is likely to result in poor overall survival rates for HCC. However there are very few Indian studies reporting survival in a sizable group of HCC patients.^12,13,18,19 The NCRP study also reported that less than one fourth of the HCCs in India present in a localized stage.¹¹ One must bear in mind that registry data may focus only on the stage and not the liver function, which is an equally important component of HCC staging and has a bearing on fitness for treatments.

With improved coverage of HBV vaccination and availability of better treatments for HCV infection, along with rising prevalence of obesity, type 2 diabetes mellitus and MASLD, we may see a further evolution in the epidemiology of HCC in the coming years. We therefore have to rethink strategies for early diagnosis and treatment of HCC to improve outcomes.

Rationale for surveillance

HCC causes significant morbidity, mortality, and is responsible for major healthcare expenditure in patients with chronic liver disease (CLD) worldwide, including India. It is the main cause of death even in patients with compensated CLD.²⁰ More than 90% of HCC occurs in patients with pre-existing cirrhosis secondary to chronic Hepatitis B, C and NAFLD.²¹ This is a potentially identifiable population for targeted surveillance.

Data from many cohort studies and a randomized trial have demonstrated significant reduction in disease specific mortality in patients with surveillance-detected HCC compared to those without.^22,23 These points satisfy the Prorok postulates for cancer screening and surveillance. Thus, the current guidelines from major liver societies across the world suggest surveillance for HCC using abdominal USG with or without the tumor marker Alpha Fetoprotein (AFP). These non-invasive tests are cost-effective and have high acceptability to the screening population.^24,25

Definitions for early-stage HCC are similar in various guidelines. The Indian National Association For Study Of The Liver (INASL) modified Barcelona-Clinic Liver Cancer (BCLC) staging system defines very early-stage disease (stage 0) as single tumor <2 cm and early-stage disease (Stage A) as single tumor between 2 and 5 cm or 2–3 nodules ≤3 cm size with preserved liver function and performance status. Surgical resection, tumor ablation (Radiofrequency ablation [RFA]/Microwave ablation [MWA]) and Liver transplantation are curative options for early HCC with a 5-year survival rate above 70%.²⁶

A surveillance programme should aim at diagnosing these very early or early-stage cancers. Six monthly USG and AFP have been consistently shown to be cost effective in screening for early HCC. This includes the gain obtainable in terms of quality adjusted life-expectancy and costs of screening and diagnostic tests, tools utilized for staging, and HCC treatment.²⁷ A caveat for the benefit of HCC surveillance is, of course, availability of and access to the recommended treatments.

On the flip side, advanced HCC as defined by BCLC stage B, C and D has limited treatment options and none of these are curative. Presence of significantly impaired liver function, suboptimal performance status or both can further limit treatments. Trans-arterial chemo/radio embolization (TACE/TARE) and systemic treatment options like immunotherapy are not available for many patients mostly due to access and cost constraints. Drug related adverse events and complications of portal hypertension like variceal bleed are additional concerns while considering treatment for individuals with advanced disease as these may result in frequent hospitalisations and worsen the financial and emotional burden. Many patients are only offered best supportive care with potential survival of weeks to months. Thus, HCC must be diagnosed at an early stage where curative treatments are possible to improve outcomes.

However, there are two different concepts of what constitutes early stage HCC. The pathologic definition refers to a lesion in the early stage of carcinogenesis and is associated with excellent prognosis.²⁸ The concept of stepwise carcinogenesis (low-grade dysplastic nodule becoming a high-grade nodule, then early HCC, and finally classical HCC) provides the rationale for this approach (Figure 1). Pathological early HCC is typically hypovascular with irregular margins on diagnostic imaging and contains portal elements without significant architectural distortion. Diagnosis and management at this stage can lead to more than 90% curative treatment rates as demonstrated in the Japanese series.^29,30 This is in contrast to the well defined hypervascular ‘classical HCC’ which is HCC in the early clinical stage and is referred to by the Western and Asian guidelines excluding Japanese.

Figure 1.

Multistep carcinogenesis in HCC.²⁸ a. Hyperplastic nodule. b. Low-grade dysplastic nodule. c. High-grade dysplastic nodule. d. Nodule in nodule type HCC (well differentiated). e. Well differentiated HCC. f. Moderately differentiated HCC focus in well differentiated HCC. g. Moderately differentiated HCC.

Differentiation between dysplastic nodules and early HCC on imaging was difficult using USG and Computed tomography (CT) scans. However, with the advent of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (EOB-MRI) the differentiation is possible (early HCC appears as a hypointense lesion and a dysplastic nodule appears as an iso- or hyper-intense lesion on the hepatobiliary phase) with a diagnostic accuracy of ≥95%.²⁸ This has been included in the surveillance strategy in Japan which has seen significant success in diagnosis and treatment of early stage HCC with some of the best reported outcomes in the world.³¹ Thus, robust HCC surveillance programmes once established should ideally aim at diagnosing cancer at a pathological early stage and not just a clinical early stage to achieve best possible outcomes.

Current surveillance guidelines

The European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) guidelines recommend that individuals at high risk of developing HCC should be entered into surveillance programmes. The most important determinant is the risk of developing HCC in the target population. Other factors to be considered are age, comorbidities, performance status and compliance to surveillance protocol. The incidence rates of developing HCC ranges from 0.2 to 8% depending upon the cause of CLD and are summarised in Table 1.^32,33 The threshold for incidence of HCC in the risk groups for surveillance to be cost effective, was traditionally 1.5%. However recent studies of modeling and cost effectiveness have suggested that this could be as low as 1%.³² The risk of HCC for patients with HCV-related cirrhosis who develop sustained virologic response (SVR) after DAA treatment is lowered, but not eliminated. Hence guidelines suggest continued surveillance for HCC in this population. The evidence in NASH and HCV without cirrhosis is low and benefit is questionable.³⁴ Surveillance interval is determined largely by rate of tumor growth (doubling time), incidence in risk population and cost effectiveness. Based on these a surveillance interval of 6 months is considered most appropriate and is recommended widely. A shorter interval of 3 months did not show clinical benefit and a longer interval of 12 months is unable to detect early tumors in a curable stage.³⁵

Table 1.

Annual Incidence of HCC in High-risk Populations.^{32,33,43,49,50}

Population	Annual incidence of HCC
HBV cirrhosis	3–8%
HCV cirrhosis	3–5%
NASH cirrhosis	2–4%
ALD-related cirrhosis	2.1%
Stage 4 PBC	3–5%
Hemochromatosis	>1.5%
HBV without cirrhosis	0.2–0.6%
HCV stage III fibrosis	<1.5%
NAFLD without cirrhosis	<1.5%

Abbreviations: ALD, Alcohol-related liver disease; HBV, Hepatitis B virus; HCC, Hepatocellular carcinoma; HCV, Hepatitis C virus; NAFLD, Non-alcoholic fatty liver disease; NASH, Non-alcoholic steatohepatitis; PBC, Primary Biliary Cholangitis.

All major societies recommend surveillance for patients with Child A and B cirrhosis of any etiology, and for Child C cirrhosis of any etiology who are listed for liver transplantation. There are some differences between the guidelines in recommendations for surveillance in patients without cirrhosis. Most guidelines recommend surveillance for chronic HBV infection with increased risk for HCC according to risk scores such as PAGE-B or based on age and ethnicity. Some guidelines also recommend surveillance for patients with advanced fibrosis irrespective of the etiology.^32,33

Recommended Screening Tests and Interval

The screening test recommended by all guidelines is abdominal USG. This is based on a high accuracy of USG in picking up liver tumors (sensitivity 58–89%; specificity >90%).³⁶ USG is less effective in picking up early tumors with sensitivity of only 63%.³⁷ It is the most acceptable imaging modality with proven cost effectiveness in diagnosing tumors before clinical presentation.²⁷ The sensitivity of USG may be lesser in individuals with NAFLD due to inadequate visualization. The recommended scan is a standard B-mode USG. Contrast enhanced ultrasound (CEUS) is not recommended by most guidelines for surveillance due to its inability to scan the entire liver. It may have better utility as a second-line imaging for characterization of indeterminate or inconclusive liver nodules diagnosed on conventional imaging.^38,39

Multiple tumor markers have been used for HCC surveillance. Serum AFP levels are commonly used for surveillance of HCC because of wide availability and relatively low cost. AFP is however a suboptimal test for surveillance in view of fluctuating levels in patients with cirrhosis with multiple reasons for the same including flare of HCV or HBV infection, exacerbations of the underlying liver disease, or occurrence of HCC. Very low sensitivity in early HCC (15–20%) also precludes its use as a sole surveillance tool.⁴⁰ Another tumor marker Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) also known as Des-gamma carboxyprothrombin (DCP) is a highly specific marker for HCC. It outperforms AFP in diagnosis of early HCC.⁴¹ Combination of AFP and PIVKA-II has been shown to be better than either markers alone. Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) can differentiate elevated AFP due to HCC from non-HCC conditions. It is calculated as a subfraction of AFP. However, it has its own drawbacks including low sensitivity when serum AFP levels are low (<10 ng/mL) due to which it has to be combined with other markers.⁴² The different screening tests are compared in Table 2.

Table 2.

Comparison of Screening Tests.^36,37,40, 41, 42

Tumor marker	Sensitivity (%)	Specificity (%)	Sensitivity for early HCC (%)
AFP	41–65	80–94	20
AFP-L3	39–75	83–90	27
PIVKA II	41–74	70–100	48
USG	58–89	97	63

Abbreviations: AFP, Alpha Fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein; HCC, Hepatocellular carcinoma; PIVKA-II, Prothrombin Induced by Vitamin K Absence or Antagonist-II; USG, ultrasonography.

The EASL guidelines recommend 6 monthly USG abdomen for HCC surveillance whereas AASLD suggests use of USG abdomen with or without AFP levels.^32,33 The Asian Pacific Association for the Study of the Liver (APASL) and INASL guidelines recommend both USG abdomen and AFP level to be checked every 6 months.43, 44, 45 The Japanese Society of Hepatology (JSH) guidelines recommend a combination of USG abdomen with multiple tumor markers 3–6 monthly based on risk stratification.^46,47 This regular JSH surveillance protocol may be combined with dynamic CT/MRI for extremely high-risk patients.⁴⁷ The different society guidelines are summarised in Table 3, Table 4.

Table 3.

High Risk Populations in Whom HCC Surveillance is Recommended as per Current Guidelines.^26,32,33,43, 44, 45^,49

Society	Super high-risk group	High-risk group
INASL	–	Cirrhosis of any etiology ▪Child A/B ▪Child C who are listed for liver transplantation Non-cirrhotic: ▪Chronic HBV with increased risk for HCC according to risk scores ▪Chronic HCV with advanced fibrosis.
APASL	–	Cirrhosis of any etiology Non-cirrhotic: Chronic HBV infection (HBsAg positive) – depending on ethnicity and age
AASLD	–	Cirrhosis of any etiology ▪Child A/B ▪Child C who are listed for liver transplantation Non-cirrhotic: Chronic HBV infection – depending on country of origin and risk score
EASL	–	Cirrhosis of any etiology ▪Child A/B ▪Child C who are listed for liver transplantation Patients without cirrhosis ▪Chronic HBV with increased risk for HCC according to risk scores ▪F3 Fibrosis regardless of etiology
JSH	Cirrhosis with HBV or HCV	Cirrhosis of any other cause Chronic HBV or HCV infection

Abbreviations: AASLD, American Association for the Study of Liver Diseases; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBV, Hepatitis B virus; HCC, Hepatocellular carcinoma; HCV, Hepatitis C virus; INASL, Indian National Association for Study of the Liver; JSH, Japanese Society of Hepatology.

Table 4.

Comparison of Various HCC Surveillance Guidelines.^26,32,33,43, 44, 45^,49

Society	Recommended surveillance modality	Recommended surveillance interval
INASL	US + AFP	6 months
APASL	US + AFP	6 months
AASLD	US ± AFP	6 months
EASL	US	6 months
JSH	High-risk group: US + AFP + AFP-L3 + PIVKA III	High-risk group: 6 months
	Super high-risk group: CT/MRI	Super high-risk group: 3–4 months CT/MRI every 6–12 months

Abbreviations: AASLD, American Association for the Study of Liver Diseases; AFP, Alpha Fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; INASL, Indian National Association for Study of the Liver; JSH, Japanese Society of Hepatology; PIVKA-II, Prothrombin Induced by Vitamin K Absence or Antagonist-II.

Despite multiple published guidelines by various scientific societies, there is no significant improvement in longitudinal outcomes in HCC. The challenge facing us presently is to identify the reasons why the guidelines in their present form are not resulting in the diagnosis of significant numbers of early HCC tumors and deliberate on possible solutions to improve this situation. The primary problem even in countries like the US and Europe is underuse of HCC surveillance.

Lessons from Japan

The Japanese model is the only successful surveillance protocol which has shown consistent improvement in diagnosis of early HCC along with significant improvement in survival rates over many years. Very early and early stage cancer account for 67% of all newly diagnosed HCC in the Japanese population whereas advanced stage (BCLC C and D) are only 6%. Results of Nationwide Surveillance of HCC by Japanese Liver Cancer Association (JLCA) shows that more than 94% of all new HCC do not show extrahepatic spread and the majority have single tumors.⁴⁷ Hence a significant number of patients are eligible for curative treatment options, primarily RFA or MWA. The median OS in patients with HCC is close to 80 months in Japanese Cohorts which is 4–8 times more than similar populations elsewhere in the world.⁴⁸ Current JSH guideline recommends performing two or more tumor markers (AFP, AFP-L3, PIVKA-II) and USG every 6 months in high-risk patients (those with chronic hepatitis B or C or non-viral cirrhosis), and every 3 months in extremely high-risk patients (HBV and HCV related cirrhosis) with an option of dynamic CT or MRI every 12 months.⁴⁹ This could be a template for us to design similar protocols if we are to achieve similar results. Although the same protocol may not be feasible in India, it can be suitably modified with emphasis on use of blood-based biomarkers with rigorous evaluation.

Challenges in adopting a strategy for surveillance for HCC in India

HCC surveillance results in early tumor detection, a potential for curative therapy, and thus improved survival in patients with cirrhosis.⁵¹ Despite this fact, surveillance is under-utilized with the consequences of most HCC being detected when symptomatic, generally at an advanced stage. Surveillance is a multi-stage process. It starts from patient identification, physician awareness, patient compliance, utilization of appropriate tests at appropriate intervals, their interpretation and does not end with diagnosis. Once diagnosed, the patients should receive appropriate curative therapies in a timely manner for surveillance to have its greatest impact.

Under-utilization of surveillance is not only seen in developing countries but also reported from developed countries. In a study from the USA, using data from the Surveillance, Epidemiology, and End-Results registry (SEER) -Medicare databases, less than a third of patients with cirrhosis received regular surveillance.⁵² In another recent study, HCC surveillance was underused in more than 80% of patients with cirrhosis.⁵³ The authors reported failures in many aspects of the screening process including ‘lack of clinician orders, lack of patient compliance, or even, lack of cirrhosis recognition’. A Systematic Review and Meta-Analysis of the Use of HCC surveillance in patients with cirrhosis reported under-utilization of HCC surveillance in clinical practice [pooled estimate for surveillance use- 24.0%, 95% confidence interval, (18.4–30.1)], particularly among patients with ALD or Non-alcoholic steatohepatitis (NASH)-related cirrhosis and those not followed up in subspecialty gastroenterology or hepatology clinics.³ More patients from subspecialty clinics underwent surveillance as compared to those from population-based cohorts (73.7% versus 8.8%, P < 0.001).

Issues Related to Surveillance in India

Issues related to surveillance start with identification of the at-risk population and that is perhaps the biggest hurdle! Despite the increasing prevalence of MASLD reported from India, the commonest etiology of CLD and HCC is still chronic HBV infection.⁵⁴ As per the National Family Health Survey-4 data, the national seroprevalence of Hepatitis B was 0.95% (0.89–1.01).⁵⁵ An effective HBV vaccine has been available since the 1980s and integrated in the universal immunization program in India since 2007 in a staged manner. However, vaccination coverage in India, especially the birth dose (vital for preventing early transmission) is suboptimal although the numbers have been steadily increasing over the past decade. The World Health Organization's (WHO) global hepatitis strategy, endorsed by all WHO Member States, aims to reduce new hepatitis infections by 90% and deaths by 65% between 2016 and 2030. However, in view of the less than ideal vaccination coverage and seroconversion rates, it is unlikely that seroprevalence rates will change significantly in India in the near future.

Thus, what we have is a huge at-risk population with chronic HBV infection that needs to be diagnosed and treated and evaluated for HCC surveillance. Mass screening for HBV can be expensive to implement and impractical and thus, a large proportion of these cases remain undiagnosed until development of symptoms. Individuals with HBV related HCC are younger and may not have cirrhosis. Surveillance needs to be started in those with chronic HBV infection at an earlier age and even in those without cirrhosis. In the absence of patient and provider education, many eligible patients will not be offered surveillance resulting in non-diagnosis or delayed diagnosis of several HCCs. Antiviral treatment suppresses viral replication and the risk of developing HCC in patients with chronic HBV infection but does not eliminate the risk and these patients still need surveillance.

Although chronic HCV infection is responsible for a small proportion of HCC cases in India, it cannot be ignored. DAAs have revolutionised the management of HCV infection in the last decade making HCV treatment efficient and safer as compared to interferon-based regimens. However, despite high SVR rates, the risk of HCC persists. A recent meta-analysis estimated HCC incidence after HCV cure of 0.5 and 2.1 per 100 person-years in patients with F3 fibrosis and cirrhosis respectively.⁵⁶ The authors also reported that the HCC risk decreased with each year of follow-up after HCV cure in patients with cirrhosis. Thus, surveillance in patients with chronic HCV infection with an SVR following DAA treatment may need further risk stratification and refinement for resource optimization.

Thus there is a significant variation in the risk of HCC in patients with chronic HBV and HCV infection. This risk changes with the stage of fibrosis, treatments and response. Universal surveillance as per standard guidelines may not be the correct approach here and predictive scores could potentially help in stratification and focusing on those with a higher risk. Many clinical and artificial intelligence (AI)- based predictive scores have evaluated risk prediction of HCC prognosticating the risk for both HBV and HCV related liver disease but validation and generalizability are issues.57, 58, 59, 60

MASLD is an increasingly common cause of CLD in India although it is frequently under-diagnosed. MASLD related HCC is equally prevalent in men and women and almost 30–40% MASLD related HCCs develop on a background of advanced fibrosis without cirrhosis so identification of eligible individuals for screening is difficult.⁸ USG is a suboptimal surveillance tool in MASLD due to change in echotexture of the liver and coexisting obesity. Finally, even despite the hurdles for surveillance, were we to detect early stage HCC, concurrent obesity and Type 2 diabetes mellitus may pose challenges in fitness for certain therapies and it is likely that the benefit of immunotherapy may be lower than expected. MASLD related CLD thus needs a different strategy for surveillance and cannot be clubbed with non-viral etiology. There are no specific surveillance recommendations for CLD associated with other causes including alcohol, and routine surveillance guidelines apply to these individuals.

Awareness, healthcare availability, access and costs are common hurdles in surveillance. India lacks an organized, structured health care system with standard referral pathways. General physicians as well as specialists see patients with CLD. Although screening guidelines for HCC in patients with cirrhosis are standard, a lack of physician awareness could lead to lack of universal adoption of screening guidelines. Also, a significant number of HCCs are now seen in non-cirrhotic patients who require risk stratification for surveillance, which can only be done competently in specialty clinics. Speciality clinics with standard operating procedures are the need of the day as literature shows that patients from subspecialty gastroenterology/hepatology clinics have higher rates of undergoing surveillance.³

USG, the standard recommended test, is non-invasive, widely available and relatively inexpensive. Yet, most patients do not get screened and very few HCCs are diagnosed in an early stage. There is also a lack of quality assurance in USG due to the huge variability in available expertise. USG is an operator dependent modality and without a high-quality scan, surveillance may not yield benefits. The cost of the USG, though relatively low, is also generally borne by patients out of pocket due to lack of health insurance or long waitlists for appointments at government centers. This adds to the financial burden of many poor patients especially as it needs to be repeated 6 monthly.

Another major challenge is access to healthcare. Most tertiary centers see patients visiting from all corners of India due to a paucity of adequate health care facilities in many states. This results in higher financial burden and large number of dropouts from treatment. India has a significant number of migrant population. In the absence of a national level network of specialty clinics with a common, shared registry, there is no transition of care or continuity of treatment for patients with CLD who migrate from one place to another.

Last, but not the least, what happens if we do manage to implement HCC surveillance and diagnose early HCC? There are currently very few specialized centers in India that can offer state of the-art treatments at reasonable costs to those diagnosed through surveillance pathways. Many patients travel significant distances to access advanced healthcare and incur severe and even catastrophic financial toxicity in the process. The costs of treating early stage HCC from ablative therapies to resection or transplant are prohibitive for most Indians. Coverage of these treatments by existing national health schemes to varying extents may ease the burden but other logistic hurdles may still deter many patients from seeking care and undergoing appropriate treatments.

The lack of awareness in both patients and health care providers about who should be subjected to surveillance for HCC is probably the biggest barrier for eligible patients to be offered surveillance in India. Healthcare availability and access is another significant bottleneck for both surveillance and treatment of those diagnosed through surveillance pathways. Lack of awareness can still be addressed by focused awareness programs but the healthcare issues will need strong policy changes and are likely to take years to resolve, if at all.

How do we improve surveillance and diagnosis of early HCC in India?

The task at hand of improving HCC surveillance and outcomes is a daunting one with multiple challenges. A focused approach at identifying potential areas for high impact solutions is needed today. It is incumbent upon the Gastroenterology and Hepatology community to take this up as a priority.

Identifying the Gaps

The first step is to identify the gaps between evidence or guidelines and its implementation in clinical practice across diverse healthcare systems and regions in India. This requires surveys on knowledge, attitudes, and practices of clinicians towards surveillance of HCC.⁶¹ It is important to train the internal medicine, gastroenterology and hepatology residents and fellows at an early stage about HCC prevention and surveillance. Small group meetings focused on surveillance for HCC can help disseminate the information better. Identifying a core team of interested clinicians to take up this task on the lines of World Gastroenterology Organisation (WGO)- Train the trainers (TTT) programme is a good starting point in this direction.⁶² This should aim to establish a group with well-defined targets and accountability both in the short term as well as long term and would provide an immense thrust to HCC surveillance.

A Common National Database

The second step is to create a credible national database of patients with CLD. This can start initially with Hepatitis B and C related cirrhosis and gradually extend to other areas like MASLD and ALD. A unique CLD dashboard can be created as part of a pan-India collaborative network which should be updated periodically based on patient follow ups. This will provide easy access for nationwide data extraction and planning.⁶³ Use of unique health IDs as used during the Covid 19 pandemic with or without linking to the Aadhaar number can help rapidly identify and reach patients to facilitate surveillance and improve compliance. This will also prevent loss of follow ups when patients migrate to other towns or seek care at other centers and ensure continuity of care for the patients. This model is already being used in the public health sphere for national vaccination, tuberculosis, and HIV programmes.64, 65, 66 Direct patient contact and reminders regarding surveillance are likely to improve engagement and use of mobile and internet technology can reduce the urban-rural disparities to some extent.

Rethink Strategy

The next step is to re-evaluate the existing surveillance protocols. The present hospital-based approach is less likely to succeed in improving the pickup rate. The Dutch national bowel cancer screening programme used a home-based stool test which increased the participation rate to 71% of at-risk population leading to increase in pick up of early colorectal neoplasia.⁶⁷ A similar model using multiple lab-based biomarkers and digital algorithms is likely to improve patient compliance by reducing the need for hospital or clinic visits, reducing loss of wages especially for those from lower socioeconomic classes, thus reducing the dropout rates.⁶⁸ USG is an operator dependent modality and could have wide quality variations. CT and MRI are expensive, may not be easily accessible and suffer from quality issues due to variability of the machines used. Hence an imaging free approach is appealing in this setting.

A nation-wide HCC surveillance program was established around the 1980s in Japan. PIVKA-II and AFP-L3 in addition to AFP were approved in 1989 and 1996, respectively. As a result of early detection of small HCC, HCC outcomes in Japan are best in the world.³¹ With the availability of newer biomarkers a purely USG-free approach may be an acceptable option and should be explored in India for surveillance and early diagnosis of HCC.^69,70

A Japanese study of 270 HCC patients with serum AFP levels less than 20 ng/mL, combining AFP-L3% and PVKA-II biomarkers detected 49% of all HCC patients with a size less than 2 cm. Similar retrospective studies in Korea and Germany showed impressive results using a combination of these three biomarkers for diagnosis of early HCC with a sensitivity of 75–85% and specificity of 85–90%.71, 72, 73 The question about the added advantage of using three biomarkers compared to just two was answered by a Thai study which showed that two biomarkers AFP and PIVKA-II are effective in surveillance for early HCC.⁷⁴

Consider/Evaluate Newer Digital Algorithms

The use of newer digital algorithms is likely to bring a radical change to HCC diagnostics in the near future and a USG-free approach may become a viable option. Two products from Roche – GALAD (Gender, Age, AFP-L3, AFP, DCP) and GAAD (Gender, Age, AFP, DCP) have recently been launched for diagnosis of HCC. They combine multiple biomarkers with demographic factors in a proprietary digital algorithm to provide a composite score. The GALAD score has shown excellent overall accuracy (AUROC values of 95%, sensitivity of 92%, and specificity of 85%). These results are maintained in patients with early HCC (AUROC of 92%, sensitivity of 92%, and specificity of 79%).⁷⁵

Preliminary studies show that these algorithms combined with USG are significantly better than USG plus AFP combination for early HCC diagnosis.⁷⁶ These results have been validated in multiple cohorts with similar impressive results in HBV, HCV and NAFLD related HCC.^77,78 A recent multicenter international study evaluating GAAD for the detection of early-stage HCC reported a sensitivity of 71.8% with 90.0% specificity. The AUC for differentiation between early-stage HCC and CLD was 91.4% with 70.1% sensitivity and 93.7% specificity with low rate of false positives regardless of disease stage and etiology.⁷⁸ Similar results were reported by Huang and colleagues.⁷⁹ These algorithms have been tested for cost effectiveness and early data suggests GALAD and GAAD performed alone are cost effective compared to USG plus AFP.⁸⁰

The last challenge will be to ensure that strategies are cost effective.⁸¹ A lab based strategy can reduce need for hospital visits and USG which will significantly reduce the cost burden. A campaign to do large scale testing on two days of the year (World hepatitis day and World cancer day) using medical camps can further reduce the cost. Use of information technology and AI based tools in patient recall and scheduling of tests can potentially provide large health care cost benefits.

Recommendations for the way forward

India is projected to have a rising cancer incidence in the coming years pushed by changing population age demographics along with changing prevalence of lifestyle related risk factors. Breast, oral cavity, and cervix-uteri are the three most common sites of cancers in India for which there are ongoing national screening programs. However the percentage of men and women who have ever undergone screening through these programs is abysmally low at <2%.⁸² In view of such low numbers for established screening programs for common cancers in India, developing surveillance programs for HCC is definitely a daunting task. However, it is not insurmountable.

A retrospective cohort-control Indian study performed at two liver clinics in Ludhiana and Mumbai compared the stage at diagnosis and treatment of HCC diagnosed through surveillance pathways and without.⁸³ The authors reported that surveillance led to detection of HCC at an early stage and patients with an earlier stage of HCC had significantly higher survival than those diagnosed at a later stage. However, only 28% of eligible patients received treatment. This study highlights two important facts- that HCC surveillance is possible in India and can detect early stage cancers but it can only improve survival if diagnosed patients have access to appropriate treatment. This underscores the fact that development of a surveillance program must be accompanied by capacity building and improving access to affordable treatments for any benefit to be seen. We may also need a risk stratification based on etiology due to the differing risks and challenges in screening of viral vs non-viral etiology of CLD (Table 5).

Table 5.

Proposed HCC Surveillance Strategy.

Risk stratification	Risk group	Surveillance protocol
Very high risk	HBV and HCV related Cirrhosis	3/6 monthly AFP + PIVKA-II Or GAAD +/− USG +/− Annual abbreviated MRI
High risk	Cirrhosis due to other etiology Chronic HBV with Male >40 y  Female >50 y  Family h/o HCC  Not on antiviral therapy	6 monthly AFP + PIVKA-II Or GAAD +/− USG
Low risk	NASH without Cirrhosis	Biomarkers only Surveillance interval uncertain

Abbreviations: AFP, Alpha Fetoprotein; HBV, Hepatitis B virus; HCC, Hepatocellular carcinoma; HCV, Hepatitis C virus; NASH, Non-alcoholic steatohepatitis; PIVKA-II, Prothrombin Induced by Vitamin K Absence or Antagonist-II; USG, ultrasonography; GAAD, Gender Age AFP, DCP.

A tailored strategy has to be developed for India taking into account local factors and learning from past mistakes and failures. Evaluating ideas that have worked elsewhere and tweaking them to enable local implementation in a resource-scarce setting like ours may be the way forward. Access to care is a big barrier in India which can only be addressed in a staged manner. The COVID pandemic ensured widespread use of digital platforms in healthcare from virtual consultations to virtual multi-disciplinary team meetings (MDTs) and the same can be used to increase the access and outreach of surveillance programs by trying to bring the clinic to the patient wherever possible.

We need change at multiple levels- patient, physician and system level. Educational interventions can improve both patient and physician awareness and should be a thrust area especially in specialty gastroenterology and hepatology clinics. National societies can help raise awareness on HCC surveillance and promote health-seeking behavior using both print and social media platforms. Occasions like World cancer day and World hepatitis day could also be used for raising awareness and participation in surveillance programs. Physicians should receive training to run specialty clinics using standard operating procedures (SOPs) for diagnosis, management and surveillance in patients with CLD and a referral pathway to tertiary centers may help standardize care and plug the gaps. Specialty clinics have been shown to improve utilization of surveillance for HCC.³ They may also ensure adequate risk stratification for surveillance which would lead to judicious use of resources and best patient outcomes.

Lastly, we need significant changes in the health system. A national surveillance program for HCC may not be feasible or viable presently but a stepwise plan of staged inclusion of different high-risk groups in HCC surveillance starting with those with cirrhosis of viral etiology and then moving on to other high-risk groups seems achievable with some efforts. A pan-India collaborative network with a national database using unique health IDs will enable cross-center referrals and decrease attrition or loss to follow ups and strengthen the surveillance program. This would also align with the Ayushman Bharat Digital Mission (ABDM) that aims to support the integrated digital health infrastructure in India. However, privacy and data security are issues which will need to be tackled for digital platforms to succeed. As technology access improves across India, more advanced technologies such as artificial intelligence and machine learning could be integrated in the risk stratification and diagnosis, if found to be beneficial.

Existing resources can be utilized and upgraded for capacity building in a staged manner for both workforce and infrastructure. This should cover basic clinical expertise for specialities of gastroenterology, surgery, hepatology and radiology and also advanced facilities like interventional radiology and liver transplantation. Costs of surveillance and treatment of early stage HCC have to be critically considered and appropriate recommendations should be provided to the government for inclusion in various insurance schemes to ensure that diagnosed patients get treated. Finally, centers of excellence could be identified or developed to function as treatment and training nodes as part of a hub and spoke model linked to smaller centers (Table 6).

Table 6.

Steps to Improve Surveillance and Diagnosis of Early HCC in India.

1. Identify a core special interest group with set targets and accountability

2. Evaluate existing surveillance practices and target the deficiencies identified, e.g. focused interventions to improve awareness, etc.

3. Collaborative research on predictive models and cost effectiveness to identify high risk groups

4. Identify centers of excellence, develop a hub and spoke model for one center to offer training and proctorship to several others for capacity building

5. Strengthen surveillance practise a.Identify high risk groups to implement surveillance b.Identify screening tests: ensure quality and identify those (i.e. MASLD, obesity) who may need alternative tests c.Repeat surveillance at recommended intervals d.Ensure referrals for treatment to those diagnosed through surveillance e.Use technology: national database, virtual clinics, patient reminders

Abbreviation: MASLD, Metabolic dysfunction-associated steatotic liver disease.

The barriers to HCC surveillance differ across different healthcare settings and we need Indian data to gain clarity on our problems and find pragmatic solutions. The first step could be formation of a special interest core group that will do a SWOT analysis and formulate an action plan. A critical evaluation of surveillance practices in India is a good starting point. Development and/or validation of predictive scores or models in Indian patients with CLD related to different risk factors can direct risk stratification and ensure judicious use of scarce resources to identify those who may benefit most from surveillance. These individuals could then be fast tracked into surveillance programs. Our strength in information technology should be utilized for creation of national databases and virtual clinics improving access and decreasing attrition. The economic impact of HCC surveillance should be rigorously assessed by Indian studies using Indian data so as to refine our surveillance practise. Collaborative Indian trials are the need of the day as we cannot continue extrapolating western data citing lack of Indian studies. Multicenter collaboration is the way ahead for us to make any meaningful impact on outcomes for patients with CLD and HCC.

Credit authorship contribution statement

Both authors were involved in conceptualization; methodology; project administration; writing of the original draft as well as reviewing and editing it.

Conflicts of interest

All authors have none to declare.

Funding

None.