Multidisciplinary consensus recommendations for management of hepatocellular carcinoma in Middle East and North Africa region

Hepatocellular carcinoma (HCC) is a growing health concern projected to cross over a million cases worldwide by 2025. HCC presents a significant burden of disease in Middle East and North African (MENA) countries due to a high prevalence of risk factors such as hepatitis C and B infections and rising incidence of non‐alcoholic steatohepatitis and non‐alcoholic fatty liver disease. In August 2022, an advisory meeting consisting of experts from 5 MENA countries was convened in an attempt to provide consensus recommendations on HCC screening, early diagnosis, current treatment modalities and unmet medical needs in the region. Data were collected from a pre‐meeting survey questionnaire and responses analysed and presented during the advisory meeting. This review summarizes the evidence discussed at the meeting and provides expert recommendations on the management of HCC. The 2022 update of Barcelona clinic liver cancer (BCLC) staging and treatment strategy and its implementation in the MENA region was extensively discussed. A key consensus of the expert panel was that multidisciplinary care is crucial to effective patient management that results in better clinical outcomes and overall survival of the patient. The panel recommended the use of predictive and early response biomarkers to guide clinicians in arriving at more effective therapeutic decisions. The experts also emphasized the role of robust screening/surveillance systems, population‐based registries, effective referral pathways and standardization of guidelines to ensure the successful management of HCC in the region.


| INTRODUC TI ON
2][3][4][5] It is currently the sixth most common and the third most lethal malignancy worldwide with an increasing incidence and prevalence in Asia. 6In Egypt, HCC is the most common cancer-related cause of mortality and morbidity. 7The incidence of HCC increases progressively with advancing age in all populations, peaking at around 70 years of age. 8,91][12][13][14][15] Long-term follow-up studies have reported that approximately 1%-8% of patients with cirrhosis develop HCC per year with a higher proportion seen in HCVinfected cirrhotic patients (3%-8%) than HBV-infected cirrhotic patients (2%). 16,17e Middle East and North Africa region (MENA) region differs from the western population in incidence, prevalence, risk factors, disease course and fatality rates seen in HCC owing to the unique cultural, ethnic and economic diversities. 18e high prevalence of risk factors and the growing disease burden of HCC is further compounded by challenges and barriers in the effective implementation of screening strategies and dearth of region-specific epidemiological and disease presentation data.
In this review, we discuss the available literature on screening and early detection of HCC in the MENA region and its associated challenges, management strategies for intermediate and advanced stage HCC and future actionable insights to optimize patient journey of HCC in the MENA region.This article will also evaluate gaps and provide recommendations for practising primary care physicians, subject matter experts, stakeholders, and decision-makers to improve the screening and management of HCC in the MENA region.

| ME THODOLOGY AND PRE-MEE TING SURVE Y
In August 2022, an expert panel meeting consisting of 12 experts from Egypt, the United Arab Emirates (UAE), Qatar, Jordan and the Kingdom of Saudi Arabia was convened in Cairo, Egypt in an attempt to provide consensus recommendations on screening, early diagnosis, current treatment modalities and unmet medical needs in HCC in the MENA region.The panel was intended to provide a multidisciplinary approach to optimizing HCC patient journey through inputs from specialists in hepato-gastroenterology, hepatic surgery, interventional and diagnostic radiology, medical oncology and radiation oncology.The objectives for the meeting were to review current practices of screening, diagnosis and management of HCC patients, and discuss the disease burden of HCC and knowledge gaps and related challenges in the MENA region.
Data were collected from a pre-meeting survey questionnaire and responses analysed and summarized to be presented during the expert panel meeting.and its implementation in the MENA region was extensively discussed.A key consensus of the expert panel was that multidisciplinary care is crucial to effective patient management that results in better clinical outcomes and overall survival of the patient.The panel recommended the use of predictive and early response biomarkers to guide clinicians in arriving at more effective therapeutic decisions.
The experts also emphasized the role of robust screening/surveillance systems, population-based registries, effective referral pathways and standardization of guidelines to ensure the successful management of HCC in the region.

K E Y W O R D S
BCLC, cirrhosis, hepatocellular carcinoma, multidisciplinary team, surveillance

Key points
• HCC is the sixth most common and the third most lethal malignancy worldwide.
• High prevalence of potential risk factors of HCC in MENA region.
• Lack of effective screening and early diagnosis strategies across MENA region.
• Early-stage disease is treated with surgery (resection and liver transplantation), and locoregional therapies such as ablation.
• Systemic treatment is most commonly used for advanced HCC that includes ICI atezolizumab and bevacizumab and TKI such as sorafenib.

| Risk factors associated with HCC in the MENA region
The region has reported some of the highest prevalence rate and disease burden associated with HCV infection in the world.0][21][22] However, two successful strategic programs have been introduced by the Egyptian government to address the burgeoning HCV disease burden in Egypt.
The national HCV treatment program using direct-acting antiviral agents resulted in 40% of the total HCV-infected population being treated with a cure rate of over 90%.Similarly, the national HCV screening and treatment program successfully screened 49.6 million persons over a period of 7 months, and identified 2.2 million HCV-seropositive persons and referred them for evaluation and treatment. 23,24[27] In Saudi Arabia, approximately 12 million individuals will be diagnosed with non-alcoholic fatty liver disease (NAFLD) by 2030.
Similarly, the cases of advanced liver disease and HCC secondary to NAFLD/NASH, are projected to double by 2030, with an annual incidence of liver-related deaths of 4800. 28e prevalence of HBV infection in the MENA region (0.6%-8%) is higher than in Western Europe and North America (<1%). 29The prevalence rates ranged from 1.5% and 1.72% in Egypt, UAE and Jordan to 3.02% in KSA. 30 The results from the global burden of disease study of 2017 reported an increasing trend in the incidence rate of HCC in the MENA region. 31The age standardized incidence rate (ASIR) of HCC in the region has increased by 11.91% from 1990 to 2017 with Egypt and Qatar reporting the highest ASIR and age standardized mortality rate of HCC (Table 1). 31,32though the main cause of HCC in MENA has been chronic viral hepatitis; the dramatic increase in the incidence rate of NASHrelated HCC may lead to a change in aetiological trend of HCC from chronic viral liver diseases to non-viral liver diseases in the near future.The highest increase in ASIR of NASH-related HCC from 1990 to 2017 was observed in Egypt (+89.8%). 31In a global burden of HCC study, HCV infection was the predominant risk factor in Egypt (>50%), however HCV contributed to 25%-50% cases in Jordan, Qatar, KSA and UAE.On the contrary, HBV contributed to 5%-10% of HCC cases in Egypt as compared to 25%-50% cases in Jordan, Qatar, KSA and UAE. 32ALD as a contributing risk factor was seen in <5% of HCC cases in the MENA region.
TA B L E 1 Incidence and mortality rate of HCC and Underlying disease conditions (1990-2020).4][35] In Egypt, approximately 46.3% females are obese in comparison to approximately 22.5% of males. 36 some countries such as Egypt, exposure to inorganic compounds like pesticides and fertilizers has been suggested to be an independent risk factor for HCC. 37Similarly, dietary aflatoxin is a known risk factor for HCC. 38e responses obtained from the experts indicate an increasing trend in the incidence of HCC in the MENA region.Respondents indicated that the most important clinical risk factor for the development of HCC is HCV, however, NASH is emerging to be the next most significant risk factor (Figure 1).Some experts also noted cryptogenic factors and unknown aetiology as risk factors for HCC development.

| Rationale for HCC screening and barriers in effective implementation
Overall survival outcomes are critically influenced by the stage at which HCC is diagnosed and is also the most important factor that determines treatment decisions and management strategies. 39 treatments and have significantly poorer survival outcomes. 40,41nce, the goal of a screening program for HCC is to identify high-risk individuals and to detect tumours at early stages in order to initiate timely curative treatments, achieve improved long-term survival and optimize patient journey.6][47][48][49] Patients with liver cirrhosis comprise more than 80% of newly diagnosed HCC cases and form the largest at-risk group for developing HCC.sensitivity and specificity for early-stage HCC.A substantial proportion of HCC patients are reported to have normal AFP levels even at an advanced stage of the disease. 56,57False elevations in AFP are often seen in viral hepatitis or other liver masses such as cholangiocarcinoma and may require prudence in interpretation. 58Multiphase, contrast-enhanced imaging modalities such as computerized tomography (CT) or magnetic resonance imaging (MRI) are not recommended as first-line surveillance methods due to unavailability, higher cost, radiation exposure, and poor patient tolerance. 59American Association for the Study of Liver Diseases (AASLD) recommends CT or MRI only in select patients with inadequate ultrasound, while European Association for the Study of the Liver (EASL) recommends using CT or MRI in high-risk patients on the liver transplant waiting list. 45,46However, these newer imaging tools may not be cost-effective for all patients.Hence in order to reinforce screening programs in those who remain at higher risk, use of a HCC risk stratification system optimizes the allocation of medical resources in a cost-effective manner.Cancer predictor models include routine parameters estimating coexisting comorbidities, persisting liver inflammation or function impairment, and results of non-invasive tests which are combined into HCC risk scoring systems. 60This system enables stratification according to various liver cancer incidences and categorization of patients into low, intermediate or high HCC risk probability groups.All major international guidelines recommend long-term surveillance of these patients using semi-annual ultrasound.Predicting incidence of HCC in this system will lead to individualized management with cost-effective surveillance tools such as contrast-enhanced imaging techniques or circulating biomarkers. 61A prospective United Kingdom study identified risk factors and biomarkers of HCC and developed the "GALAD" score consisting of gender, age, AFP-L3, AFP, and des-gamma-carboxy prothrombin providing accurate prediction rates of HCC regardless of stage. 62A scoring system developed by the HCC Multidisciplinary Clinic-Cairo University, was an easy to calculate, accurate, cost-effective score for HCC

| Current practices and emerging novel methods in HCC screening and surveillance
Liver ultrasonography (US) is the recommended imaging tool and serum alpha-feto protein (AFP) is a predictive tumoral biomarker most widely used for surveillance of HCC. 50Liver US every 6 months with or without AFP level is universally accepted modality for HCC surveillance due to low cost and ease of availability. 46,47,51,52Although liver US is an effective screening tool, its sensitivity is determined by a number of factors including operator knowledge and skill, gender, obesity, and the underlying aetiology of liver disease. 53,54Contrast-enhanced ultrasound is used to accurately characterize focal lesions detected on US in terms of tumour boundaries and vascularity. 55AFP also has limited sex (male = 6, female = 0), and platelet count (≥200 000/μL = 0, 100 000-199 999/μL = 1, <100 000/μL = 2) A total sum of ten or more indicates intermediate or high risk of hepatocellular carcinoma.

Consensus Recommendations on HCC Screening Protocols
• All adult patients with chronic liver disease including cirrhosis, chronic HBV and HCV infections, and NASH/ NAFLD with advanced fibrosis (fibrosis stages 3 and 4) are considered at high risk for developing HCC and should be enrolled in a screening and surveillance program.
• Patient compliance is the biggest challenge in implementing effective screening strategies.Lack of physicians' adherence to guidelines and unavailability of resources also proves to be a hindrance to effective screening programs.
• The promotion of specific educational programs for practitioners, clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.
prediction in chronic HCV patients with advanced liver fibrosis and was superior to other scores for predicting HCC, with a sensitivity of 90% and a specificity of 80.6%. 63predictive model called general evaluation score (GES) was developed to determine the risk of developing HCC after using directacting antivirals.The GES score proved successful in stratifying patients into low-risk, intermediate-risk and high-risk. 64cently, liquid biopsies, such as circulating tumour cells, circulating tumour DNA, and extracellular vesicles, have been researched emerging as novel biomarkers that can be used in precision medicine in patients with HCC adding to the armamentarium of screening and surveillance tools of HCC. 49 Egypt, considering HCV is the main etiological factor for liver cirrhosis, followed by HBV, liver elastography has gained momentum as a reliable method for assessing liver stiffness through Fibroscan and being an early predictor of susceptibility for development of HCC with high sensitivity and specificity. 65An abbreviated MRI protocol was found to be superior to AFP and ultrasound in detecting small hepatic focal lesions in post-HCV cirrhotic patients in Egypt. 66

| Diagnosis of HCC: current practices and recommendations
The diagnosis of HCC is generally based on a combination of clinical, laboratory, radiographic and histopathologic parameters and presentation.Patients with an abnormal screening test, (presence of a liver nodule in abdominal US or high serum AFP [>20 ng/mL]) should be referred for further diagnostic evaluation. 1,51Lesions <1 cm in diameter can be followed up with a repeat US after 3 months.For lesions >1 cm in diameter, either quadruple-phase CT or dynamic contrast-enhanced MRI should be performed (Figure 2). 67Histopathological features suggested by the International Consensus Group for Hepatocellular Neoplasia include stromal invasion, increased cell density, intratumoral portal tracts, unpaired arteries, pseudo-glandular pattern and diffuse fatty changes. 68Atypical appearance in radiological images warrants an ultrasound-guided biopsy or a second contrast-enhanced study. 51e size of the nodule is often considered a deciding factor in determining future management plan.Small nodules are generally indistinguishable from cirrhotic nodules and should be ideally followed • Although it is considered ideal to perform a tissue biopsy prior to initiating systemic therapy, the general consensus is that if the imaging is conclusive (whether or not supported by elevated levels of AFP), there is no need for biopsy.In patients where liver transplantation is considered and with LI-RADs four classification, a liver biopsy is indicated as is the practice in Qatar.

| OVERVIE W OF CURRENT MANAG EMENT S TR ATEG IE S OF H CC IN MENA REG ION
Optimal management of HCC is determined by multiple complex factors that include tumour size, number, location, and patient characteristics, such as underlying liver function and performance status. 67Similarly, the prognosis of patients with HCC is determined not only by the aetiology but also significantly influenced by the level of functional liver failure. 72The treatment algorithm for HCC continues to evolve with the emergence of novel systemic therapies, updated criteria for resection, newer locoregional therapies and, availability of multiple radiation therapies. 67fferent staging systems are used to select the best treatment option for HCC patients.The most commonly used staging systems for HCC is the Barcelona Clinic Liver Cancer (BCLC) staging system, which combines tumour characteristics (number of tumours, tumour size and presence of portal vein invasion or extrahepatic metastasis) with an assessment of the severity of liver disease and functional status of the patient. 44,51,73,74 3). 78e BCLC algorithm is followed for the treatment of patients with HCC in the MENA region.for small HCC where RFA is not available, or when RFA is considered not suitable due to tumour location (e.g.adjacent to the gallbladder, hepatic hilum, or large vessels).
Advanced stages of HCC or disease conditions unsuitable for TACE and TARE are treated with external beam radiation therapy in the form of stereotactic body radiation therapy or proton beam therapy, systemic targeted small molecule tyrosine kinase inhibitors (TKIs), and checkpoint inhibitor immunotherapy. 70 the MENA region, most patients present at advanced stages (BCLC B, C and D) due to absence or inefficient screening and surveillance programs and hence have limited therapeutic options, as evidenced by the responses of the pre-meeting survey (Figure 4).
In case of surgical intervention, the Milan criteria (1 lesion greater than or equal to 2 cm and less than or equal to 5 cm, or up to 3 lesions, each greater than or equal to 1 cm and less than or equal to 3 cm) governs the patient's suitability as a candidate for liver transplantation. 83 MENA region (Figure 5).

| Transarterial Chemoembolization (TACE)
TACE is the treatment of choice for some patients with intermediatestage HCC and non-resectable HCC and is associated with significantly improved overall survival rate. 45,46,79,88,89Several studies support TACE for providing both embolization of the tumour-feeding blood vessels resulting in a strong cytotoxic and ischemic effect to the tumour and chemotherapy by infusion of a cytotoxic agent, all along keeping a good hepatic reserve for better survival. 90,91TACE is instrumental in down-staging before liver transplantation in patients who are outside of the Milan criteria for liver transplantation and has been demonstrated in an Egyptian study. 92In Qatar, a retrospective analysis found improved median survival of over 2 years in patients who received TACE as first-line treatment. 86e to less than favourable safety profile, stringent patient selection is crucial to the success of TACE when treating HCC.The general consensus is that patients with an ECOG PS of 2 or more, or with severe hepatic decompensation (Child-Pugh C or decompensated Child-Pugh B) will not benefit from TACE and may experience severe adverse effects.Additionally, patients with advanced-stage disease and who develop progression are not candidates for TACE due to the risk of developing liver failure. 93Although TACE can be repeated a number of times, an optimum "on-demand" treatment with a 1 or 2 month interval between sessions and ceasing TACE after 2-3 unsuccessful sessions is recommended. 94e prognosis of HCC patients undergoing TACE is also highly variable.Various prognostic scores have been developed to standardize assessment across institutions, however none of them have been unanimously accepted and included in guidelines.Assessment of retreatment with TACE score is based on the deterioration of liver biochemistry following initial TACE and the presence of radiological response to treatment. 95This score can aid in identifying patients eligible for repeated sessions and determine when TACE should be stopped, and systemic therapy adopted.7][98] Additionally, the six-and-twelve score

| Transarterial radioembolization (TARE)
TARE or selective internal radiation therapy is a relatively newer procedure using percutaneous selective intra-arterial administration of microspheres loaded with a radioactive compound (most commonly yttrium-90).[103] Transarterial therapies are the preferred treatment options in BCLC B in the MENA region (Figure 6).TARE can safely be used in portal vein thrombosis as well, unlike TACE.The albumin-bilirubin grade permits assessment of the impact of liver function on survival and determines candidates for TARE. 97 Sorafenib is contraindicated in severely compromised liver function.In a retrospective observational study conducted in Qatar, sorafenib was well tolerated in both Child-Pugh A and B group and survival was improved but it was more pronounced in the Child-Pugh A group. 110Treatment-related adverse events (TRAEs) are commonly seen with TKIs that range from hand-foot-skin reaction, fatigue and increased blood pressure to more severe pancreatitis, increased risk of haemorrhage and pancytopenia.[113][114][115] Lenvatinib is an alternative to Sorafenib and has been approved as the first-line treatment for patients with advanced HCC with a higher radiological response rate and better PFS, but comparable overall survival (OS) to Sorafenib.Regorafenib, that targets angiogenesis, tumour cell as well as the fibroblast growth factor (FGF) receptor more intensely than sorafenib, can be used post-progression on sorafenib and is approved as the second-line treatment option for patients with advanced HCC. 115,116 They also significantly improved median progression-free survival rate along with a better safety profile.
Additionally, recent real-world evidence with lenvatinib report survival comparable to atezolizumab and bevacizumab combination with a focus on patients with NASH. 117bozantinib, a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymalepithelial transition factor (MET) receptor, and the "anexelekto" (AXL) receptor tyrosine kinase has been approved for the treatment of advanced HCC after failure of sorafenib. 118The duration of treatment with TKIs varies between 6 months to 1 year.In case of nonresponsiveness, the duration may be shortened to 2-3 months.
There are limited studies evaluating the survival benefit of Sorafenib in Child-Pugh B population.In a study conducted in patients with HCC with Child-Pugh B disease comparing sorafenib, pravastatin and sorafenib-pravastatin combination, neither sorafenib nor pravastatin seemed to improve overall survival with median OS reported to be similar in all arms.However, potential benefit of Sorafenib was noted in ALBI grade 1/2 sub-population.The use of bevacizumab increases the risk of bleeding.
Esophagogastroduodenoscopy is imperative in screening and evaluating the grade of oesophageal varices commonly seen in cirrhosis and HCC.Patients with varices that are grade 2 or higher should be treated for varices before initiating therapy and should not be considered for treatment with antivascular endothelial growth factor therapies.
Among ICI monotherapy options, pembrolizumab and nivolumab (both anti-PD-1) had received accelerated approval for patients with advanced HCC who have been previously treated with sorafenib. 121,122volumab approval was later withdrawn by the FDA based on negative from the phase III CheckMate-459 trial.
Single-agent ICI treatment provides benefits (overall response rate) in fewer HCC patients, and PD-L1 status does not appear to be a crucial factor in HCC, thus combination therapies have appeared as new therapeutic strategies; moreover, angiogenesis contributes to immunosuppression.
Ramucirumab (RAM), a human monoclonal antibody that inhibits activation of VEGFR2, showed a significant survival benefit, by reducing the risk of death by 29% in HCC pts with AFP ≥400 ng/mL who progressed on or were intolerant to sorafenib. 123mbination ICI therapies have been more successful than have concluded and results presented. 125,126In both trials combination therapy failed to demonstrate survival benefits compared to monotherapy.
Superior efficacy profile notwithstanding, ICI therapy can impact and create an imbalance in the immune system that can result in a wide range of immune-related adverse events, which are generally manageable but occasionally can be life-threatening.A metaanalysis that summarized the current evidence on toxicity profiles of TKIs and ICIs among patients with HCC, found serious adverse events to be lower with ICIs than with TKIs, while liver toxic effects were similar. 127e cost of ICIs is a limiting factor for their use in the MENA region and since TKIs are covered by most governments, majority of patients choose this option.
With the advent of multiple potentially superior therapeutic options, clinicians are now increasingly faced with the challenge of optimum patient selection for the best treatment. 87There is however unavailability of suitable biomarkers to guide the development of checkpoint inhibitors and their combinations in HCC.

| PERSPECTIVES ON MULTI DIS CIP LIN ARY CARE: CHALLENGES AND WAY FORWARD
Effective management of HCC that improves clinical outcomes requires a multidisciplinary treatment (MDT) approach, encompassing the specialities of hepatic surgery, diagnostic and interventional radiology, medical oncology, radiation oncology, hepatology, and palliative care. 128,129The 2022 BCLC staging and treatment strategy

Consensus Recommendations on HCC Management Modalities in MENA region
• All cases should be discussed in multidisciplinary team.
• Liver resection can be considered as the treatment of choice for early-stage HCC patients with no cirrhosis.
• For patients with early-stage HCC (BCLC 0 and BCLC A) in whom surgery is contraindicated, local ablative techniques are optimum such as RFA.
• TACE is the preferred treatment option for BCLC B patients.However, contraindications for TACE include ECOG PS 2 or more, severe hepatic decompensation, and portal vein thrombosis.
• For patients with BCLC C HCC, treatment options could be atezolizumab + bevacizumab or STRIDE regimen as first-line therapy.
• For patients with BCLC C HCC and a well-preserved liver function, sorafenib or lenvatinib, a first-line alternative for atezolizumab and/or bevacizumab can be used.
• All patients with liver cirrhosis should undergo endoscopy to mitigate the risk of bleeding associated with bevacizumab.Since oesophagogastric variceal bleeding is a common complication in patients with HCC, the morbidity and mortality caused by hematemesis is more significant than the progression of HCC itself.
• Nonselective beta blockers can be started immediately for small varices and are effective in reducing portal hypertension almost immediately.Band ligation is an effective therapeutic option for achieving both initial haemostasis and preventing further bleeding episodes.
• Development of predictive and early response biomarkers that can guide clinicians in therapeutic decisions.

ACK N O WLE D G E M ENTS
The authors would like to acknowledge Dr. Sushma Jayan and Dr.

Suvarna Chavan Labcorp Scientific Services and Solutions Private
Limited for medical writing support which was done in accordance with Good Publication Practices 2022 guidelines.

FU N D I N G I N FO R M ATI O N
This work was funded by AstraZeneca FZ LLC.

CO N FLI C T O F I NTE R E S T S TATE M E NT
IW has received research grants, lecture honoraria and travel sup-

Centre(s) of Excellence
• There is a considerable gap in the expertise of MDT composition in the MENA region, especially in private practice and rural geographies.
• Emphasis on the role of MDT across all institutions to optimize treatment decisions which would result in better clinical outcomes, survival rates, and quality of life in patients of HCC.
• Constituting MDTs in all centres in the MENA region with the basic disciplines of interventional and diagnostic radiologists, hepatologists, medical oncologists, and hepatic and transplant surgeons.
• Establishing centres of excellence that provide guidance and expertise on state-of-the-art HCC diagnosis, treatment, and current research to the newly developed centres through knowledge-sharing virtual sessions.
• Creating a robust patient registry in HCC collating the diagnostic aspects, disease course, treatment modalities, clinical outcomes and prognosis.
Curative treatments such as surgical resection, ablation (radio-frequency ablation, microwave ablation), or liver transplantation, are the treatment choices for early stage, small localized tumours, whereas for intermediate stages local therapy (trans-arterial chemoembolization [TACE], trans-arterial radioembolization [TARE]) are recommended.However, patients having extensive disease with large, multifocal tumours, macrovascular invasion, or extrahepatic metastasis are given palliative

3.2. 1 |
Commonly encountered barriers in the implementation of HCC screening in the MENA region The effectiveness of HCC screening and surveillance programs in improving clinical and survival outcomes in high-risk patients is governed by multiple factors that are both physician and patient-related.These factors range from accuracy of screening tests to physicians' awareness, adherence to guideline-driven recommendations, patient's awareness about screening tests, patient compliance, cost of screening tests, and access to resources.The surveillance rates are also sub-optimal in lower socioeconomic populations, and among ethnic minorities.In the MENA region, implementation of screening programs is sub-optimal.There is lack of awareness among patients and reduced compliance to screening procedures.In addition, physicians' adherence to guidelines and unavailability of resources are a major hurdle.Misinterpretation of the imaging reports by the first clinical contact of the patient/primary physician due to the highly variable presentation of HCC results in delayed referral to specialized centres.There is a dearth of epidemiological data related to the MENA region, which is a hindrance to exact estimation of disease prevalence.F I G U R E 1 Risk factors associated with HCC.HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, non-alcoholic steatohepatitis.
up with a repeat US every 3 months.The National Comprehensive Cancer Network Guideline recommends repeat US plus AFP every 3-6 months.The guidelines for confirmatory diagnosis of HCC based on methods excluding biopsy have been updated several times over the years.Currently accepted guidelines suggest liver nodules larger than 1 cm in size should be evaluated with dynamic contrast-enhanced CT / MRI or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), a liver-specific contrast agent MRI. 69Presence of radiological hallmarks such as arterial hypervascularity and venous/late washout should be considered positive for HCC.A diagnosis pathway that does not consider the size of the nodule suggests dynamic imaging regardless of tumour size.The 2014 Japanese Society of Hepatology Guideline included Gd-EOB-DTPA MRI as a tool for first-line surveillance and diagnosis of HCC. 70The Liver Imaging Reporting and Data System (LI-RADS) provides standardization for HCC imaging in diagnosis, and treatment response assessment and has been integrated into the most recent HCC clinical practice guidance by the AASLD. 71Consensus Recommendations on Current HCC Screening Practices in MENA region • Most patients with HCC present at advanced stages despite effective screening and surveillance programs.The reasons are multifactorial such as lack of patient awareness and compliance, non-availability of insurance coverage, inadequate follow-up of patients with abnormal screening test results, and sub-optimal screening programs.• Current screening programs consist of ultrasonography in combination with biomarkers such as AFP, done every 4 to 6 months in at-risk patients.However, due to increased number of HCC patients with normal AFP levels, novel blood-based diagnostic biomarkers should be developed, especially in case of small HCCs.• Several risk scores, based on a risk stratification system, have been developed over the years to adequately quantify varying levels of risk of HCC development in at-risk patients.Their use should be prospectively evaluated in large studies before being recommended in practice.Consensus Recommendations on Diagnostic Criteria• Due to wide variation in the sensitivity and specificity of techniques that results in a small proportion of cases being misdiagnosed, standardization of the technique, establishment of minimum reporting requirements, and constitution of a dedicated team among radiologists is recommended, especially because treatment modalities are heavily dependent on accurate diagnosis.•For patients without cirrhosis and a focal lesion in the liver or for whom HCC diagnosis remains indeterminate on imaging, liver biopsy could be considered for a definite diagnosis.
Child-Pugh grade, a three-category scale (A, B, C), with C indicating the most severe compromise of liver function, determines the liver functional reserve and the physical status is determined by corresponding Eastern Cooperative Oncology Group (ECOG) performance status.Depending on the stage and severity of the disease, HCC can be classified as resectable, transplantable, unresectable, or metastatic. 40,41,75-77Patients are categorized into five categories: Stage 0 (very early stage), Stage A (early stage), Stage B (intermediate stage), Stage C (advanced stage), and Stage D (terminal stage) (Figure 7,79,80 Surgical resection and liver transplantation are recommended for patients with early-stage HCC and are the first-line treatment options for BCLC Stage 0 and A. Ablative techniques, including percutaneous ethanol injection (PEI), microwave ablation (MWA) or radiofrequency ablation (RFA), catheter-directed TACE or radio-embolization (TARE) are often resorted to next. 81,82Although PEI is inexpensive and safe with low mortality and morbidity, it has been largely replaced by MWA and RFA over the past decade.PEI can still be offered in some settings

F I G U R E 4
79,85-87 A large proportion of patients in the MENA region are diagnosed at a stage of HCC where surgical therapies are no longer viable due to the extent of the disease, poor hepatic reserve, or coexistent morbidities.The most widely available ablation techniques are percutaneous ethanol injection, RFA and MWA.RFA is recommended for small tumours ≤3 cm and very early HCC (BCLC 0).However for patients with HCC in proximity such as gallbladder, stomach, colon, or other viscera, percutaneous ethanol injection or surgical resection (if feasible) should be the choice of treatment. 87F I G U R E 3 Treatment Landscape of HCC.AFP, alpha-feto protein; ALBI, albumin bilirubin; BSC, best supportive care; MELD, model for end-stage liver disease; LT, liver transplant; PS, performance status; TACE, trans-arterial chemoembolization.Stages of presentation (in %) of HCC (BCLC) seen in MENA.BCLC, Barcelona clinic liver cancer; HCC, hepatocellular carcinoma.

(
presented as the sum of tumour size [cm] and number) predicts patient survival in ideal candidates of TACE more accurately than other models With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 prognostic categories predicting overall survival.99Persistent viable targeted lesion(s) after consecutive treatments, new intrahepatic lesion(s) appearing after consecutive treatments, continuous elevation of tumour markers, appearance of vascular invasion or extra-hepatic spread may constitute TACE failure or refractoriness prompting its discontinuation.100

105 F I G U R E 5
Potential candidates for TARE are patients with an unresectable Child-Pugh class A HCC (good liver function), patients with portal vein thrombosis and multifocal disease.Patients with a large (>6 cm) unresectable HCC can benefit more from TARE than those with a small HCC. 104As per the updated BCLC B treatment algorithm for HCC, TACE is recommended only in patients who have preserved portal flow and well-defined nodules and TARE has not been mentioned in BCLC B treatment.The Saudi Association for the Study of Liver diseases and Transplantation recommend using TACE alone compared to using sorafenib in combination with TACE.TARE may be used as an alternative to TACE in the treatment of intermediate-stage HCC if associated with portal vein thrombosis. 87Additionally, TARE can be a suitable alternative treatment for some locally advanced-stage HCCs with the use of personalized dosimetry.Treatment modalities for BCLC A patients.BCLC, Barcelona clinic liver cancer.4.2.3 | Systemic therapies A majority of the HCC patients in the MENA region are diagnosed at an advanced stage with extensive disease and extrahepatic spread, limiting therapeutic options significantly.Experts often rely on systemic treatment in these situations despite the low safety profile and limited availability of options.TKIs, antiangiogenesis agents, and immunotherapy form the backbone of systemic treatment for HCC. 46,106In case of preserved liver function, systemic treatment options for HCC in the MENA region comprise mostly of TKIs.The TKI sorafenib is the established first-line standard systemic treatment for patients with intermediate or advanced-stage HCC who are ineligible for TACE.Sorafenib is the first drug to have shown increased survival benefits in HCC.Consequently a number of large pivotal trials showed significantly increased overall survival in patients treated with sorafenib, such as the SHARP trial, 107 the HCC registry study (GIDEON) 108 and the prospective study by Tovoli F et al 109 suggesting better management of HCC with the help of TKIs by clinicians.However, the Asian population in the SHARP trial showed comparatively lower survival rate.It is also noteworthy that the radiological response rate associated with Sorafenib is limited (<10%).

4. 3 |
Emerging role of immunotherapy in HCCIn the last few years, immuno-oncology has resulted in a paradigm shift in the treatment of HCC.Immunotherapy with ICIs, such as atezolizumab (anti-programmed death-ligand 1 antibody) and the angiogenesis inhibitor bevacizumab (anti-vascular endothelial growth factor antibody) can reverse tumour-immunosuppression, which makes the combination of anti-angiogenic molecules and ICIs a rationale treatment strategy.The combination of atezolizumab and bevacizumab was the first regimen to improve overall survival and progression-free survival in comparison with sorafenib as evidenced by the phase III IMbrave-150 trial comparing the combination of atezolizumab and bevacizumab with sorafenib in previously untreated patients with advanced HCC.120At the end of the 12 months period, 67.2% of patients in the ICI combination arm were still alive, 12% more than the 54.6% OS rate seen with sorafenib.Additionally, progression-free survival was significantly F I G U R E 6 Treatment modalities for BCLC B patients.BCLC, Barcelona clinic liver cancer; BSC, best supportive care; TACE, trans-arterial chemoembolization; TAE, transarterial embolization; TARE, transarterial radioembolization; TKI, tyrosine kinase inhibitor.longer in ICI combination group compared to Sorafenib group, HR 0.59 (95% Confidence Interval, 0.47-0.76,p-value: <.001).The objective response rate and PFS benefits in the atezolizumab plus bevacizumab-treated patients in the non-viral aetiology subgroup were consistent with those observed in the hepatitis B and hepatitis C virus aetiology subgroups, suggesting that patients with non-viral aetiology do derive clinical benefit from this treatment.
monotherapy, for example the HIMALAYA trial with STRIDE regimen consisting of a single initial dose of tremelimumab, an anti-CTLA-4 monoclonal checkpoint inhibitor and regular interval durvalumab, anti-PD-L1demonstrated superiority vs. sorafenib monotherapy in the first-line treatment of advanced HCC patients (OS HR 0.78 [96.2% CI, 0.65-0.92]and PFS HR 0.90 [95% CI, 0.77-1.05]).Durvalumab monotherapy was non-inferior to sorafenib monotherapy.Patients in the STRIDE regimen had lower risk of haemorrhage and hence endoscopy is not a pre-requisite. 124Two recent clinical trials, COSMIC-312, assessing cabozantinib plus atezolizumab versus sorafenib and LEAP-002 evaluating the efficacy of lenvatinib plus pembrolizumab versus lenvatinib plus placebo as first-line systemic treatment for advanced hepatocellular carcinoma

6 |
also highlighted the different concepts and parameters that physicians and multidisciplinary tumour boards should integrate for a personalized approach to treating HCC and introduced the concept of treatment stage migration.Criteria for identification of candidates eligible for initiation of TACE have also been further refined.Patients for whom transplantation is not feasible but who have preserved portal flow and well-defined nodules allowing selective access to tumour arteries are the only candidates for TACE.130While hepatologists are the first to diagnose and coordinate treatment modalities, interventional radiologists are involved at several stages of the management of HCC, from ablating small lesions in patients awaiting transplantation to providing transarterial therapies (TACE and TARE).Hepatic surgeons play a pivotal role in identifying the right patient candidate for resection and for liver transplantation as first-line treatment based on the Milan criteria or the up-to-7 criteria.Indications of treatment by liver surgery for hepatocellular carcinoma differ according to the guidelines.EASL guidelines recommend surgery in case of solitary lesion without vascular invasion, in well compensated patients with an MELD (model for end-stage liver disease) score <10.For AASLD guidelines, all potential resectable solitary tumours <5 cm, with or without vascular invasion, and multifocal <5 cm tumours should undergo surgery in the absence of impaired liver function.APASL guidelines enlarge the indication to all resectable tumours even those with vascular invasion and in patients with decompensated cirrhosis (Child-Pugh B).The presence of portal hypertension is not an absolute contraindication but must be balanced with liver function and the extent of the hepatectomy.131Medical oncologists are involved in the critical decision-making of the right time to initiate systemic therapies.CON CLUS ION Hepatocellular carcinoma is a considerable medical burden in the MENA region considering the high prevalence of liver diseases and viral infections.Majority of patients with HCC in the MENA region are diagnosed in the intermediate or advanced stages with poor prognosis and limited therapeutic options.Although significant progress has been achieved recently in the prevention, early detection, diagnosis, and management of patients with HCC by successfully identifying risk factors and implementing screening and intervention programs, there continues to be challenges and knowledge gaps.Region-specific evidence-based data to better understand challenges unique to the MENA region and effective strategies to address them are imperative.Establishing robust screening/surveillance systems, population-based registries, a multidisciplinary approach for diagnosis and treatment and better availability of therapeutic options are crucial to the success of effective management of HCC in the region.
AGA: In addition to the above recommendations, patients with NAFLD with non-invasive tests (NIT) showing evidence of advanced liver fibrosis or cirrhosis should be considered for HCC screening.Abbreviations: AASLD, American Association for the Study of the Liver Diseases; AGA, American Gastroenterology Association; 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; LT, liver transplantation.a PAGE-B (platelet, age, gender, hepatitis B) score is calculated using age (16-29 = 0, 30-39 = 2, 40-49 = 4, 50-59 = 6, 60-69 = 8, ≥70 = 10), TA B L E 2 Indications and risk factors for HCC surveillance.AASLD EASL APASL 1.All adults with cirrhosis, except for Child-Pugh class C patients ineligible for liver transplant 1. Cirrhotic patients, Child-Pugh stage A & B 1.All adults with cirrhosis, except for Child-Pugh class C patients ineligible for liver transplant 2. High-risk patients with HBV a Asian men age >40 a Asian women age >50 a Family history of HCC a African ancestry 2. Cirrhotic patients, Child-Pugh stage C awaiting LT 3. Non-cirrhotic HBV patients at intermediate or high risk of HCC according to PAGE-B a classes for Caucasians 4. Non-cirrhotic F3 patients based on individual risk assessment 2. High-risk patients with HBV a Asian men age >40 a Asian women age >50 a Family history of HCC a African ancestry age >20 Note: from Mena Pharma, Pharco, Novartis, Arena, Abbvie, Astra Zeneca, Marcyrl Pharmaceuticals, Bayer, Eva Pharma, and Roche.SA has received research grants from Amgen.AS has received honoraria and has participated in the DSMB of Astra Zeneca, Bayer, Roche.AA has received research grants, lecture honoraria and travel support from Astellas, Novartis Sandoz Astra Zeneca, Bayer, Elhekma, Bayer, Johnson and Johnson, Medilab, Surgymed.AH has received lecture honoraria and travel support from Astra Zeneca, Boston Scientific, Roche and Sirtex.GE has received research grants, lecture honoraria and travel support Marcyrl pharma, Pharaoina Pharma, Mena Pharma, Abbvie, Gilead, Bayer, Roche and Eva Pharma.Nat Rev Dis Primer.2021;7(1):1-28.doi:10.1038/s41572-020-00240-3 2. Cancer (IARC) TIA for R on.Global Cancer Observatory.Accessed November 2, 2022.https://gco.iarc.fr/ 3. Sung H, Ferlay J, Siegel RL, et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 1.LlovetJM, Kelley RK, Villanueva A, et al.Hepatocellular carcinoma.