Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, and due to substantial morbidity and mortality, has proven a significant global health-economic burden. Treatment options are broad and include surgical approaches (i.e., transplantation and resection), radiological (i.e., percutaneous ablation, and trans arterial approaches) and systemic therapies, though treatment response often remains poor. As such, clinical decision making requires a multidisciplinary approach to improve treatment strategy after consideration of the patient's tumor stage, liver function, and performance status. Current systemic cytotoxic therapies for non-surgical candidates have largely remained unchanged over the last decade. Systemic therapies have extended life expectancy by up to 3 months but not without potential notable adverse effects that often limit their use. However, even if patients have necessary access to best treatment, survival outcomes remain concerningly poor. Improved understanding of the pathogenic role of advanced liver fibrosis and wider cancer biology is spearheading the development of targeted immunogenic therapies that appear to offer real promise. Importantly, limiting progression to cirrhosis and early detection of HCC in at risk groups, alongside best use of currently accessible therapeutic options, remains key across global healthcare systems. The focus of this review is to critically assess all current published literature, encapsulating the prevalence, diagnosis, and management of HCC, whilst looking ahead to the potential future therapeutic directions in HCC management.

Full text

J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
1 Volume 8; Issue 01
Review Article
Incidence, Diagnosis, and Management of
Hepatocellular Carcinoma: Current Perspectives
and Future Direction
Balasubramaniyan Vairappan1*, Gavin Wright2, T.S. Ravikumar3
1Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research,
Pondicherry-605006, India
2Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, UK
3AIIMS, Mangalagiri, Andhra Pradesh, India
*Corresponding author: Balasubramaniyan Vairappan, Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal
Institute of Postgraduate Medical Education and Research, Pondicherry-605006, India.
Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma:
Current Perspectives and Future Direction. J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
Received Date: 11 February 2023; Accepted Date: 21 February 2023; Published Date: 24 February 2023
Journal of Digestive Diseases and Hepatology
Vairappan B, et al. J Dig Dis Hepatol 8: 189.
www.doi.org/10.29011/2574-3511.100089
www.gavinpublishers.com
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, and due to substantial morbidity and
mortality, has proven a signicant global health-economic burden. Treatment options are broad and include surgical approaches
(i.e., transplantation and resection), radiological (i.e., percutaneous ablation, and trans arterial approaches) and systemic
therapies, though treatment response often remains poor. As such, clinical decision making requires a multidisciplinary approach
to improve treatment strategy after consideration of the patient’s tumor stage, liver function, and performance status. Current
systemic cytotoxic therapies for non-surgical candidates have largely remained unchanged over the last decade. Systemic
therapies have extended life expectancy by up to 3 months but not without potential notable adverse effects that often limit their
use. However, even if patients have necessary access to best treatment, survival outcomes remain concerningly poor. Improved
understanding of the pathogenic role of advanced liver brosis and wider cancer biology is spearheading the development
of targeted immunogenic therapies that appear to offer real promise. Importantly, limiting progression to cirrhosis and early
detection of HCC in at risk groups, alongside best use of currently accessible therapeutic options, remains key across global
healthcare systems. The focus of this review is to critically assess all current published literature, encapsulating the prevalence,
diagnosis, and management of HCC, whilst looking ahead to the potential future therapeutic directions in HCC management.
Keywords: Diagnosis; Imaging; Liver Cancer; Management;
Surveillance; Systemic Therapy.
Abbreviations: AASLD: American Association for the Study
of Liver Disease; AFP: Alpha-Fetoprotein; APASL: Asia-Pacic
Association for the Study of the Liver; BCLC: Barcelona Clinic
Liver Cancer; CT: Computed Tomography; EASL: European
Association for the Study of the Liver; ECOG: The Eastern
Cooperative Oncology Group; HCC: Hepatocellular Carcinoma;
HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; LT: Liver
Transplantation; NAFLD: Non-Alcoholic Fatty Liver Disease;
NASH: Non-Alcoholic Steatohepatitis; MELD: Model for End-
Stage Liver Disease; MRI: Magnetic Resonance Imaging; TACE:
Transarterial Chemoembolization; US: Ultrasound; WHO: World
Health Organization
Introduction
Hepatocellular carcinoma (HCC) is one of the most lethal
malignancies (~830000 deaths per year) and is an important
medical problem globally. It is ranked as the fth most common
neoplasm and the second leading cause of cancer-related
mortality, with a relative ve-year survival rate of ~ 18% [1-4].

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
2Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
In Asian countries, the prevalence accounts for nearly 75-80 %
of primary liver cancers [5]. In 2020, nearly one million people
were diagnosed with liver cancer worldwide, the most dominant
form of which reported was HCC [4]. Moreover, the World Health
Organization (WHO) estimates that more than one million HCC
patients will die in 2030 [6]. The burden of HCC varies according
to demographic factors (age, gender, race/ethnicity), rarely occurs
in people before age 40, increases more than 55 years, and reaches
a peak at 70 years. Furthermore, the incidence rates among men are
three times as high as the rates among women [7]. Consequently,
due to its high prevalence, not many signicant therapeutic options
are available for advanced HCC. Therefore, improving the early
detection and prognostication of HCC patients is imperative.
Incidence
Most cases of HCC arise from cirrhosis and additional
comorbidities, and its incidence is expected to rise in the future [8,
9]. Hepatitis B virus (HBV) is a DNA virus that promotes mutation
in liver cells by inducing necroinammation and thus causes HCC
and death worldwide (33%). By contrast, hepatitis C virus (HCV)
is an RNA virus that does not integrate into the host genome and
is thus unlikely to be the primary initiator of HCC. About 90%
of HCV-associated liver cancer cases are heralded by cirrhosis,
and the annual incidence rate ranges from 0.5% to 10% [5, 10,
11]. Moreover, chronic heavy alcohol consumption (>3 drinks/
day) was associated with increased HCC risk (~16%); perhaps
no association was noticed with lower levels of consumption
(<3 drinks/day) [12]. Non-alcoholic fatty liver disease (NAFLD)
and its more severe form, non-alcoholic steatohepatitis (NASH),
is emerging as one of the leading HCC risk factors in developed
regions [13, 14]. Recent evidence has emerged that obesity-
mediated chronic inammation was also associated with an
increased risk of HCC [15, 16]. Interestingly, a diabetic individual
with obesity shows an increased risk of liver cancer [1].
Prevention
Cirrhosis and other chronic liver diseases are susceptible to
HCC, consequently, prevention may reduce the population at risk.
Prevention of HCC can be achieved with universal vaccination
against HBV infection [17]. The WHO recommends HBV vaccines
for infants and high-risk groups. A previous study has shown in
Taiwan that Nationwide HBV vaccination to infants resulted in a
36 % reduction in the incidence of HCC compared to unvaccinated
cohorts [18]. Antiviral therapies effectively reduce HCC incidence
in HBV-infected patients (HBsAg-positive), and eliminate HCV
in viremia patients, however, does not eradicate the risk of HCC
in viral hepatitis patients [7]. In this context, it has been shown
that treatment with lamivudine (100mg/day) for 5 years to chronic
HBV patients on the background of cirrhosis reduced the incidence
of HCC risk compared to placebo [19]. Interferon therapy to
HCV patients without cirrhosis had a sustained viral response
and reduced HCC risk by about 75% compared to HCV patients
with cirrhosis who do not have a sustained response to antiviral
therapy [20, 21]. Furthermore, several studies conducted in Japan
and southern Europe have shown that coffee drinking is associated
with a reduced risk of HCC [22]. Albeit the mechanism for this
protective effect remains poorly understood.
Surveillance/Screening
Surveillance and screening of HCC are tremendous
approaches to detect the disease early and reduce mortality. So far,
no high-quality randomized controlled trial has been available for
the surveillance of HCC in cirrhotic patients [2]. However, several
non-randomized studies have reported that HCC patients recruited
into a surveillance programme had a chance of early diagnosis,
more frequent curative therapy and better overall survival than
unrecruited peers [23]. The imaging and serum α fetoprotein
(AFP) measurement are the standard methods for surveillance of
HCC. However, the use of AFP is no longer recommended due
to its inadequate sensitivity (around 60%), specicity (80%) and
predictive value for surveillance testing of HCC. Recently, many
studies have identied a reliable biomarker in diagnosing AFP-
negative HCC and thus ensuring the timely initiation of treatment
(0599a pdf). Ultrasound (US) is the preferred imaging test for
HCC surveillance and has a sensitivity ranging from 60-80%
and a specicity of >90% [24, 25]. However, due to its operator
dependency and unsatisfactory diagnostic accuracy, the use of US
as a surveillance tool in clinical practice is limited [26].
Diagnosis
In general, an accurate and early diagnosis of HCC can
improve the quality of life of HCC patients. Indeed, routinely
followed clinical techniques such as imaging and histology could
only detect late-stage diagnosis of HCC [27]. Globally, AFP is used
as a conventional serum biomarker to detect HCC, albeit its levels
remain normal in 30% of advanced HCC cases [28]. Moreover,
elevated AFP is identied in benign liver diseases such as hepatitis
and cirrhosis [29]. Consequently, the American association for the
study of liver diseases (AASLD) practice guidelines no longer
recommend AFP for the early detection of HCC [10]. Currently,
many clinical and pre-clinical studies are focusing on identifying
a new biomarker for diagnosing AFP-negative HCC, which may
ensure the timely initiation of treatment. A large-scale multicenter
study shows that serum DKK1, a Wnt/β-catenin signaling pathway
inhibitor, could complement the diagnostic accuracy of AFP and
improve the identication of patients with AFP-negative HCC and
HCC from other chronic liver diseases [30]. In cirrhotic patients,
HCC can be diagnosed based on validated imaging techniques or
tissue biopsy. Multiphasic computed tomography (CT) or MRI
is the commonly used imaging technique for HCC diagnosis if
the diameter of the nodule is>1cm. However, these modalities
represent a major clinical challenge if the nodule diameter is <1cm

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
3Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
[8, 2, 4]. Biopsy in advanced liver disease is safe and overcomes
the limitations of non-invasive criteria since diagnostic certainty is
needed to ensure the appropriate use of systemic therapy [31, 4].
Childs et al. also conrmed that biopsy in advanced liver disease
predicts positivity in ~ 91% of HCC cases which proves about
9% of patients would receive inappropriate therapy in the absence
of biopsy [31, 4]. However, the sensitivity of these noninvasive
criteria is only 33% since a negative biopsy does not rule out
HCC [32]. According to the AASLD and EASL guidelines, CD34,
cytokeratin (CK) 7&19, GS, HSP70 and glypican 3 staining to
improve diagnostic accuracy. EASL guidelines also supplement
gene expression proles of glypican 3 and survivin for HCC
diagnosis. Arginase is a hepatocellular differentiation marker
shown to differentiate less well-differentiated tumor from other
liver tumors [4].
Clinical and biochemical markers
Vascular endothelial growth factor (VEGF) A and
Angiotensin II are biomarkers of angiogenesis and have been
associated with poor prognosis in HCC, albeit these markers
failed to predict response to treatment [5, 11, 4]. Furthermore,
biomarkers to predict treatment outcomes are lacking in HCC
patients undergoing immunotherapy. Of note, an inammatory
marker such as CRAFITY (CRP and AFP in ImmunoTherapY)
score is associated with survival and radiological response in
HCC patients receiving anti-programmed death (ligand) (PD-
L)1 immunotherapy but requires prospective validation [33].
The other inammatory marker, neutrophil to lymphocyte ratio
(NLR), is considered a prognostic predictor of HCC patients
undergoing transarterial chemoembolization (TACE). Heat shock
protein 90 alpha (Hsp90α), a molecular chaperone, is increased
in HCC patients and positively correlated with tumor malignancy
[34]. Compelling evidence indicates that micro RNAs (MiRs)
are aberrantly expressed in HCC. In particular, MiRs are highly
stable in circulation and can be used as a biomarker to test early-
stage HCC [35]. In addition, osteopontin, glypican-3 and protein
induced by vitamin K deciency or antagonist-II (PIVKA-II),
also known as Des-γ -carboxy-prothrombin (DCP), have been
identied as serum biomarkers for early detection of HCC [36,
37]. Recently, we identied in HCC patients that tight junction
protein zonula occludens (ZO) 1 blood levels were elevated and
correlated well with serum hsCRP levels [38]. A recent study has
shown that lens culinary agglutinin-reactive fraction of fetoprotein
(AFP-L3), a subtype of AFP, is derived from cancerous hepatocytes
used to diagnose early HCC [39]. However, AFP-L3 has not been
recognized as a conventional diagnostic indicator of HCC. Saad et
al. reported in HCV-related HCC patients (n=30) that serum levels
of annexin A4 (ANXA4) might be a promising biomarker for the
early diagnosis of HCC [40].
Prognosis assessment of HCC
Prognostic prediction is central in the management of HCC. For
HCC patients with concurrent liver disease, the benets of treating
the tumor must be balanced against the potential harms of medical
interventions already recommended to cirrhotic patients [2]. Thus,
the complexity of managing HCC appeals for a multidisciplinary
approach with expertise in hepatology, hepatobiliary surgery,
radiology, pathology, oncology, and specialized nursing [10, 11,
2]. The prognostic assessment incorporated several measures,
which include tumor burden (quantied based on the number and
size), presence of macrovascular invasion, extrahepatic metastasis,
degree of hepatic dysfunction (assessed by Child-Turcotte-Pugh
score, MELD score, ascites, portal hypertension, albumin and
bilirubin), and the Eastern cooperative oncology group (ECOG)
performance status [11, 3]. Among the serological markers, elevated
AFP level was correlated with poor prognosis and associated
with the risk of tumor reoccurrence after surgical resection and
liver transplant. Furthermore, a high DNA copy number of HBV
was associated with poor prognosis and tumor reoccurrence [11,
3]. Several staging systems have been developed to assess the
prognosis of HCC patients. The Barcelona-Clinic Liver Cancer
(BCLC) staging system has been extensively validated and is the
most widely applied staging system for HCC [5, 11, 2]. The other
externally evaluated staging systems are the Cancer of the Liver
Italian Program (CLIP), the French classication, Japan Integrated
Staging (JIS), tumor, node, metastasis (TNM), the Hong-Kong
Liver Cancer (HKLC) staging system, the Chinese University
Prognostic Index (CUIP) and the Taipei integrated scoring system.
According to the BCLC algorithm, HCC patients can be classied
into ve clinical stages, 0, A, B, C, and D, for a better treatment
approach (Figure 1) [5, 8, 11, 2, 4].
BCLC 0: a very early stage of HCC with solitary nodule ≤ 2 cm
without vascular invasion, Child-Pugh A, ECOG-PS 0.
BCLC A: early-stage HCC with solitary (>2 cm) or 2-3 nodules,
all ≤ 3 cm, Child-Pugh A-B, ECOG-PS 0.
BCLC B: intermediate stage HCC with multinodular unresectable
(>3 nodules or ≥2 nodules if any > 3cm), Child-Pugh A-B, ECOG-
PS 0.
BCLC C: advanced HCC with symptomatic tumor, unresectable,
segmental, or portal vein invasion, extrahepatic metastasis, Child-
Pugh A-B, ECOG-PS 1-2.
BCLC D: end-stage liver function with non-transplantable HCC,
Child-Pugh C, ECOG-PS 3-4.

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
4Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
Figure 1: BCLC staging and treatment approach. According to the BCLC system, HCC can be categorized into ve different stages
of prognosis that are concurrent to rst-line treatment recommendation. Indeed, to achieve the best clinical outcome, multidisciplinary
team should meet up and carefully discuss the treatment plans. End-stage liver cirrhotic patients should be considered for LT due to
precipitated liver function (high MELD and Child-Pugh class C or early stages with predictor of poor prognosis) [4,8,11]. Sorafenib
followed by regorafenib as second-line therapy are effective in HCC patients. Lenvatinib has been shown to be non-inferior to sorafenib,
however no second line therapy has been developed [4,8,11]. Moreover, Cabozantinib has been shown to be effective than placebo in
2nd and 3rd line with an improvement of OS [4,8,11]. Note: ECOG PS- Eastern cooperative oncology group performance status; HCC-
hepatocellular carcinoma; LT- liver transplantation; OS- overall survival. 1st line treatment: Sorafenib and Levatinib; 2nd line treatment:
Regorafenib, Cabozantinib and Ramucirumab.
Clinical Management
Several randomized controlled trials and cohort studies have
revealed that numerous therapeutic approaches have exhibited
survival benets for HCC [5, 8, 11, 2, 4]. It arises from multiple
etiologies, and almost 80-90% of HCC cases have underlying
cirrhosis; therefore, the therapeutic option is limited due to the
overall health status of the patients. The treatment protocol for
HCC has been based on the BCLC algorithm, underlying disease
severity, and expected benets of the major intervention [5, 8,
11, 2, 4]. In principle, asymptomatic patients with low tumor
burden and well-preserved liver function (BCLC stage 0/A) are
assigned to be treated with local curative treatments (resection,
ablation, or transplantation, depending upon the presence of portal
hypertension, number of nodules, and liver function). Similarly,
asymptomatic patients with multiple nodules and adequate
liver function (BCLC stage B) are recommended to receive
chemoembolization. In contrast, patients with portal thrombosis or
extrahepatic metastasis (BCLC stage C) are allocated to treatment
with rst and second-line systemic chemotherapies [5, 8, 11, 2,
4]. HCC patients at their terminal stage (stage D) received the
best supportive care and an estimated survival time of only three
months [2].
Surgical resection
The ideal candidates for hepatic resection are patients
without cirrhosis and an early-stage HCC (BCLC stage 0 or A),
irrespective of tumor size and well-preserved liver function. In HCC
patients with cirrhosis, hepatic resection is restricted with a single
nodule (regardless of size), Child-Pugh A with total bilirubin <1
mg/dl, absence of clinically relevant portal hypertension (without
ascites and varices), and ECOG score 0. For these patients, hepatic
resection is associated with a 5-year survival of 70% with low
postoperative mortality (<3%) [5, 10, 11, 2, 3]. However, many

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
5Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
of those 70% of patients have tumor recurrence at ve years
because the underlying chronic liver disease puts the patient at
risk of developing new HCC [41]. Surprisingly, there is no data
on adjuvant therapies to reduce recurrence in HCC patients [42].
In Asian countries and in USA, <5% of patients are candidates
for surgical resection while in Asia, a greater number of young
people with HBV-related HCC with minimal or no cirrhosis [7]. In
the setting of HCV cirrhosis, about 75-80% of patients experience
tumor recurrence following 5 years of resection [43].
Liver transplantation
Liver transplantation (LT) is recommended in HCC patients
with a limited tumor burden (the Milan Criteria – single nodule
≤ 5 cm or 2-3 nodules ≤ 3cm without vascular invasion) and not
on the hepatic resection list. LT has shown excellent survival
outcomes with a 5-year survival of 70% and 10-year survival of
50% with only a 10-15% recurrence rate at 5 years [5, 10, 11].
Indeed, the long-term outcome of LT has shown to be superior
to hepatic resection, which has a recurrence rate of 70% and a
10-year survival between 7-15% [5, 11, 3, 4]. Living donor LT is
an alternative elective procedure that can eliminate dropout and
enable LT in patients with HCC beyond the Milan criteria [43]. The
calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus
continue to remain potent immunosuppressants used in post LT
[44] and have been shown to promote HCC progression through
nonimmunologic mechanisms [43]. Moreover, the uncontrolled
clinical study revealed that sirolimus, an alternative to tacrolimus,
delay the appearance and retard the progression of recurrent HCC
[45].
Non-surgical treatment
HCC patients with different tumor characteristics or with
cirrhosis are not an ideal candidate for resection. Consequently,
non-surgical procedures such as radiofrequency ablation (RFA),
microwave ablations (MWA), percutaneous ethanol injection (PEI)
and transarterial chemo embolization (TACE) have well proven
anti-tumor effects. Image-guided ablation is restricted for small
nodules < 2 cm as rst-line treatment or as an alternative to hepatic
resection for early-stage single nodules ≤ 4 cm or 2-3 nodules ≤
3 cm [46, 43, 5, 11, 2-4]. For PEI, nodule diameter < 2 cm is still
recommended. RFA is used as a rst-line treatment for nodules
< 2 cm or as an alternate surgery for early-stage single nodules
≤ 4 cm or 2-3 nodules ≤ 3 cm [46, 43, 5, 11, 2-4]. Moreover, the
length of the hospital stay was shorter in the RFA group than
in surgical resection. RFA has shown superior to percutaneous
ethanol injection in improving OS. Indeed, RFA treatment has
demonstrated median overall survival of 60 months and a 5-year
recurrence of 50-70%. MWA has shown similar efcacy to RFA,
however, MWA showed a higher complication rate in tumors > 3
cm [46, 43, 5, 11, 2-4]. Eventually, the success rate of both hepatic
resection and PEI depends on careful follow-up and treatment of
new tumors.
Globally, TACE has been recommended as rst-line therapy
for intermediate stage HCC patients (BCLC-B), particularly those
with Child-Pugh A class cirrhosis who do not have extrahepatic
metastasis or vascular invasion [7]. A systematic review of
randomized trials for unresectable HCC showed survival benets
with TACE when compared to conservative treatment [47].
Furthermore, a systematic review of TACE showed an objective
response of 52.5% and the mortality associated was below 1%
[48]. Selective internal radiation therapy (SIRT) with yttrium-90
microspheres has recently been used as palliative treatment for
BCLC stage B HCC patients. Indeed, no phase 3 trials compare
yttrium-90 radiation therapy with TACE or other types of
treatment with respect to survival [49]. Moreover, Vilgrain et al.
showed in a phase 3 trial that SIRT to BCLC stage C HCC patients
did not improve OS as compared with sorafenib and there was
no improvement with a combination of SIRT with sorafenib when
compared to sorafenib alone [50].
Systemic therapy
More than 70% of HCC patients are not amenable to
treatment with LT or locoregional therapies and thus there is a
great need for effective systemic therapies. Systemic therapy is
the preferred treatment modality for advanced HCC patients
(BCLC-C) and intermediate-stage HCC who do not qualify for
local therapies. Over the past three decay, sorafenib was the rst-
line targeted therapy to show efcacy in advanced HCC patients.
Sorafenib hepatocellular carcinoma assessment randomized
protocol (SHARP) investigators study group showed median
overall survival (OS) in the sorafenib arm was10.7-months
compared to 7.9 months in the placebo group, representing a 31%
decrease in the relative risk of death [51]. Of note, recently, Kelley
et al. showed in a COSMIC-312 phase 3 trial, despite the lack of
improvement in OS, cabozantinib plus atezolizumab signicantly
improved progression-free survival and showed increased disease
control and lower primary progression compared with sorafenib
[52]. In addition, Kudo et al. showed non-inferiority of lenvatinib
(13.6 months) versus sorafenib (12.3 months) in terms of OS and
improvement in progression-free survival, time to progression,
and objective response rate thus, lenvatinib was superior to
sorafenib [53]. A recent phase III trial (REFLECT study) conrms
that FDA has approved Lenvatinib as rst-line systemic therapy
to advanced HCC [46, 43, 5, 11, 2-4]. Sunitinib is an oral multi-
tyrosine kinase inhibitor (TKI) approved for treating other cancers
but not recommended for HCC treatment due to safety issues and
futility reasons [54]. Brivanib alaninate, an oral broblast growth
factor (FGF)‐FGF receptor (FGFR) and vascular endothelial
growth factors (VEGFs) TKI used for advanced stage HCC with

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
6Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
the median OS was 10 months and 9.8 months in the rst- and
second-line treated groups, respectively with manageable adverse
events [55].
In addition, three phase III trials showed negative results
for primary endpoints when testing brivanib in the rst line
blinded to sorafenib, [56] in second line blinded to placebo [57]
and in combination with chemoembolization [58]. The other
TKI, linifanib, which targets VEGF and platelet-derived growth
factor (PDGF), and ramucirumab, a monoclonal antibody against
VEGFR2 [59], failed in phase III studies in rst-line and second-
line indications, respectively [60, 61]. Vatalanib, axitinib and
cediranib are new anti-angiogenic agents involved in treating
HCC, but the results are yet to come. Transforming growth factor-
beta (TGFb), c-MET inhibitors, MEK (MAP2K1) inhibitors, and
Janus kinase 2 (JAK2) inhibitors are also at the very early stage of
investigation [62].
Regorafenib, an oral multi-kinase inhibitor used as second-
line therapy, showed OS benets over placebo (10.6 months vs
7.8 months) in HCC patients who tolerated and progressed on
sorafenib in the phase III RESOURCE trial [63]. The FDA and the
European medicines agency (EMA) have approved regorafenib
to HCC patients who have already been treated with sorafenib.
Similarly, cabozantinib (CELESTIAL study) showed superior to
placebo in terms of OS (10.2 months vs 8.0 months) as second-
line therapy [5, 11, 2-4]. Very recently, an updated result of the
combination of atezolizumab + bevacizumab (IMbrave150 study)
showed survival improvement over sorafenib as rst-line therapy
(19.2 months vs 13.4 months) [5, 11, 2-4]. However, these therapies
are associated with weight loss, diarrhea, anorexia, asthenia, hand-
foot reaction, hypertension, and proteinuria. Unfortunately, in the
phase III trial, investigating a new agent or in combination with
sorafenib as rst-line or second-line therapy merely improved
overall survival and failed to demonstrate a 5-year survival benet
[5, 11, 2-4]. Therefore, the discovery of new therapeutic agents
is warranted, considering the survival benet and adverse effects.
Immunotherapy
Immunotherapy has been proven effective and safe and
improves survival rate and tolerable toxicity in HCC patients [64,
65]. The liver is a unique anatomical and immunological organ
capable of producing antigen-specic tolerance and accepting LT.
Therefore, the development of anti-tumor immunity against HCC
is synergistically hindered by the tolerogenic properties of the liver
and the immunosuppressive tumor microenvironment of HCC
[66]. The US food and drug administration (FDA) has approved
several immune checkpoint inhibitors (ICIs) for HCC and other
cancers. These ICIs and inhibitory receptors include programmed
cell death protein-1 (PD-1), or its ligand programmed cell death-
ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-
4), lymphocyte-activation gene 3 (LAG3), B and T lymphocyte
attenuator (BTLA), T cell immunoglobulin and mucin domain
containing-3 (TIM3) and T cell immunoreceptor with Ig and ITIM
domains (TIGIT) [67]. The PD1 inhibitor nivolumab was used as
the second-line therapy following sorafenib treatment to advance
HCC patients. Moreover, many countries have recommended the
PD-1 and PD-L1 inhibitors pembrolizumab and atezolizumab,
respectively, as clinical treatment options for HCC. A clinical
trial of the cytotoxic T-lymphocyte– associated protein 4 (CTLA-
4) blockade tremelimumab showed a partial response rate of
17.6% in HCC patients with HCV [68]. Antiviral treatment shows
improved liver function and histology and reduced HBV-DNA
levels in HCC patients [69]. The primary nucleoside/nucleotide
analogues (NAs), such as lamivudine treatment for HCC patients,
reduced the incidence but did not eliminate early and mid-level
HCC risk [70], however, entecavir therapy showed decreased HCC
risk [71]. Of note, Papatheodoridis etal. showed in Caucasians
with chronic HBV, following 5 years of entecavir or tenofovir
treatment reduced the risk of HCC among persons with cirrhosis,
but the overall risk was higher among cases without cirrhosis [70].
Moreover, numerous ongoing phase III trials exploring immune-
based therapies may begin their role in the management of HCC.

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
7Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
Name of biomarkers Potential Clinical application Validation Method References
Serum biomarker
Glypican 3 Diagnostic and prognostic Prospective, multi-centre phase II study [72]
AFP-L3 Diagnostic marker – AFP negative cases retrospective study [73,74]
Osteopontin Diagnostic and prognostic Prospective, multi-centre study [75]
PIVKAII Diagnostic marker – AFP negative cases large-scale, multicentre study [76, 77]
Golgi protein-73 Diagnostic and prognostic Prospective, single centre [78,74, 79]
Annexin A4 Early diagnosis Cross sectional – single centre [40]
Heat shock protein 90alpha Diagnostic marker Cross sectional multicentre study [80]
MicroRNA-4651 Diagnostic and prognostic - AFB1-positive cases case-control study [81]
miRNA classier (Cmi) a multicentre, retrospective, longitudinal case-
control study [82]
Metabolite biomarker panel Diagnostic potential at-risk populations
A Large-scale, multicentre case-control
study with
AFP false-negative patients
[83]
Dermcidin Diagnostic marker case-control study [84]
Tumor microenvironment
a) Cellular components
Tumor associated
macrophages Prognostic Retrospective, single centre [85]
Tumor-inltrating
lymphocytes Prognostic Meta-analysis [86]
b) Non-cellular components
Vascular endothelial
growth factor
Prognosis -HBV
Therapeutic target
Cross-sectional, single canter [87]
Transforming growth
factor-beta Diagnosis and Prognosis – HBV Cross-sectional, multi-centre [88]
Cancer stem cell marker
EpCAM Therapeutic potential target Retrospective, multi-centre [89]
CD90 Prognostic. Associated to drug resistance Retrospective, single centre [89]
Note: Aatoxin B1 (AFB1); miRNA classier (Cmi) containing seven differentially expressed miRNAs (miR-29a, miR-29c, miR-133a, miR-
143, miR-145, miR-192, and miR-505); Protein Induced by Vitamin K deciency or antagonist-II (PIVKA-II), also known as Des-γ -carboxy-
prothrombin (DCP); A serum metabolite biomarker - phenylalanyl-tryptophan and glycocholate.
Table 1: Biomarkers and their clinical application in HCC.

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
8Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
Name of Drugs Study outcome Clinical trial design References
Systemic therapyFirst-line therapy
Sorafenib Superior to overall survival SHARP NCT00105443
[51,90]
Lenvatinib Lenvatinib was non-inferior to sorafenib in overall
survival in untreated advanced HCC Open-Label, Phase 3 REFLECT Trial NCT01761266 [53,
91, 92]
Sunitinib
Negative outcome for HCC patients
Pronounced toxicities
Randomized PRODIGE 16 trial,
Intervention Model
An Open Label Multi-Centre Phase
2 study
NCT01164202 [93]
NCT00247676 [94]
Brivanib Negative outcome for HCC patients Multi-centre Phase III Study NCT00858871 [58]
Erlotinib Negative outcome for HCC patients Open Label, Non-Randomized NCT00287222 [95]
Linifanib
Negative outcome for HCC patients
Ongoing
An Open-Label, Phase 2 Study
An Open-label, Randomized Phase
3 Study
An Open label Randomized Clinical
Control Trial
NCT00517920
NCT01009593 [60]
NCT05391867
1. Second-line therapy
Cabozantinib Improves overall survival and progression-free
survival Phase III CELESTIAL trial NCT01908426 [96,
97]
Ramucirumab Improves survival benet phase III REACH and REACH-2
randomized trials
NCT01140347 [98,
99]
NCT02435433 [100]
Regorafenib
Improves
overall survival in patients with HCC who had
disease
progression during rst-line treatment with sorafenib
Multicentre Phase III RESORCE trial NCT01774344 [63,
101, 102]
Nivolumab ongoing Phase Ib, Open label NCT01658878
Pembrolizumab ongoing Phase II, Open label NCT02702414
Everolimus did not improve overall survival the EVOLVE-1 randomized clinical
trial NCT01035229 [103]
Surgical treatments
Liver transplantation Increases survival
Non-population based, consecutive
case
series
[8]
Surgical resection Increases survival
Non-population based, consecutive
case
series
[8]

Citation: Vairappan B, Wright G, Ravikumar TS (2023) Incidence, Diagnosis, and Management of Hepatocellular Carcinoma: Current Perspectives and Future Direction.
J Dig Dis Hepatol 8: 188. DOI: 10.29011/2574-3511.100088
9Volume 8; Issue 01
J Dig Dis Hepatol, an open access journal
ISSN: 2574-3511
Locoregional treatments
Percutaneous treatment Increases survival
Non-population based, consecutive
case
Series
[8]
Radiofrequency Increases survival Non-blinded, randomised controlled
trial,meta-analysis [8]
Chemoembolization Increases survival
Non-blinded, randomised controlled
trial,
meta-analysis
[8]
Table 2: Molecular targeted therapies for advanced HCC.
Conclusion and Future Perspectives
HCC is a growing health problem, and globally we are
expected to see over one million new cases each year by 2025.
HCC is a complex disease predominantly seen on a background
of advanced liver cirrhosis, a condition already associated with
signicant morbidity and mortality, from associated complications,
with a yearly incidence of HCC development evident in around
1-5% of patients with cirrhosis compounding the problem. In at
risk groups, early detection via a dedicated screening programme
is pivotal and has a profound impact on outcomes. Moreover, in
those later diagnosed with HCC, a multidisciplinary approach with
the necessary full complement of best treatment options, whether
surgical, radiological and/or oncological, ultimately provide best
treatment outcomes. Over the past decade, with the introduction
of global guidelines, HCC cancer networks and the introduction of
systemic therapies like Sorafenib, the clinical management of HCC
has evolved considerably, though ultimately any improvements in
outcomes remained modest. The big challenge regarding advanced
non-surgical approaches to HCC management is identifying novel
combination regimens for greater and continued improvement
in outcome in the front-line setting. Any new therapy has to be
compared to Sorafenib, which represents the gold standard for
systemic therapy in clinical trials and clinical care. However,
there is still the possibility of seeing further improvements with
Sorafenib as part of combination therapy and thus further phase III
trials are urgently needed to evaluate sorafenib as adjuvant therapy
after curative or locoregional therapies. Moreover, additional
second-line therapies are required if sorafenib is unsuccessful in
advanced stage HCC. Future trials involving effective systemic
therapies, especially immunotherapies based on (i.e., checkpoint
inhibitors) should continue to rise along with the pursuit of new
biomarkers that enable personalized and cost-effective therapeutic
stratication and advancement in managing all stages of HCC.
Declaration
We declare that we have no conicts of interest. All the
authors contributed equally to this review.
Consent for publication
All the authors provide consent for publishing the manuscript.
Acknowledgement
The author is grateful for the funding provided by the
Indian Council of Medical Research (ICMR) extramural grant
(No.5/13/83/2020/NCD/III).
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