Journal of Digestive Diseases and Hepatology

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Open Access review article

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

Balasubramaniyan Vairappan 1* , Gavin Wright 2 , T.S. Ravikumar 3

1 Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry-605006, India

2 Mid 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.

Received Date: 11 February 2023

Accepted Date: 21 February 2023

Published Date: 24 February 2023

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: https://doi.org/10.29011/2574-3511.100088

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.

Keywords: Diagnosis; Imaging; Liver Cancer; Management; Surveillance; Systemic Therapy.

Abbreviations: AASLD: American Association for the Study of Liver Disease; AFP: Alpha-Fetoprotein; APASL: Asia-Pacific 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 EndStage 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 fifth most common neoplasm and the second leading cause of cancer-related mortality, with a relative five-year survival rate of ~ 18% [1-4].

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 significant 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 necroinflammation 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 obesitymediated chronic inflammation 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%), specificity (80%) and predictive value for surveillance testing of HCC. Recently, many studies have identified a reliable biomarker in diagnosing AFPnegative 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 specificity 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 identified 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 identification 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 [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 confirmed 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 profiles 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 inflammatory 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) (PDL)1 immunotherapy but requires prospective validation [33]. The other inflammatory 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 earlystage HCC [35]. In addition, osteopontin, glypican-3 and protein induced by vitamin K deficiency or antagonist-II (PIVKA-II), also known as Des-γ -carboxy-prothrombin (DCP), have been identified as serum biomarkers for early detection of HCC [36, 37]. Recently, we identified 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 benefits 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 (quantified 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 classification, 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 classified into five 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, ECOGPS 0.

BCLC C: advanced HCC with symptomatic tumor, unresectable, segmental, or portal vein invasion, extrahepatic metastasis, ChildPugh A-B, ECOG-PS 1-2.

BCLC D: end-stage liver function with non-transplantable HCC, Child-Pugh C, ECOG-PS 3-4.


Figure 1: BCLC staging and treatment approach. According to the BCLC system, HCC can be categorized into five different stages of prognosis that are concurrent to first-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 benefits 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 benefits 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 first 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 of those 70% of patients have tumor recurrence at five 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 first-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 first-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 efficacy 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 first-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 benefits 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 firstline targeted therapy to show efficacy 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 significantly 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) confirms that FDA has approved Lenvatinib as first-line systemic therapy to advanced HCC [46, 43, 5, 11, 2-4]. Sunitinib is an oral multityrosine 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 fibroblast growth factor (FGF)‐FGF receptor (FGFR) and vascular endothelial growth factors (VEGFs) TKI used for advanced stage HCC with the median OS was 10 months and 9.8 months in the first- 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 first 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 first-line and secondline 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 factorbeta (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 secondline therapy, showed OS benefits 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 secondline therapy [5, 11, 2-4]. Very recently, an updated result of the combination of atezolizumab + bevacizumab (IMbrave150 study) showed survival improvement over sorafenib as first-line therapy (19.2 months vs 13.4 months) [5, 11, 2-4]. However, these therapies are associated with weight loss, diarrhea, anorexia, asthenia, handfoot reaction, hypertension, and proteinuria. Unfortunately, in the phase III trial, investigating a new agent or in combination with sorafenib as first-line or second-line therapy merely improved overall survival and failed to demonstrate a 5-year survival benefit [5, 11, 2-4]. Therefore, the discovery of new therapeutic agents is warranted, considering the survival benefit 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-specific 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 deathligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA4), 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 (CTLA4) 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 immunebased therapies may begin their role in the management of HCC.

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 classifier (Cmi)

a multicentre, retrospective, longitudinal casecontrol 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-infiltrating 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: Aflatoxin B1 (AFB1); miRNA classifier (Cmi) containing seven differentially expressed miRNAs (miR-29a, miR-29c, miR-133a, miR143, miR-145, miR-192, and miR-505); Protein Induced by Vitamin K deficiency or antagonist-II (PIVKA-II), also known as Des-γ -carboxyprothrombin (DCP); A serum metabolite biomarker - phenylalanyl-tryptophan and glycocholate.

Table 1: Biomarkers and their clinical application in HCC.

 

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 benefit

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 first-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]

 

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 significant 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 stratification and advancement in managing all stages of HCC.

Declaration

We declare that we have no conflicts 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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