- Committee

 • Chair of the Oncology Committee of Egyptian health council Guidelines: Prof Hussein Khaled. 

• The Oncology Committee Members: Emad Hamada, Samir Shehata, Hesham Elghazaly, Hesham Tawfik, Fouad Abuotaleb, Ebtesam Saad Eldin, Ihab Khalil, Khaled Abdelkarim, Lobna ezz Elarab, Mary Gamal, Mohamed Abdel Mooti, Mohamed Gamil, Nervana Hussein, Ola Khorshid, Omar Sherif Omar, Rasha Fahmi, Rasha Shaltout, Yousri Wasef & Yousri Rostom. 

• Chair of the HCC Scientific Committee: Yousri Rostom 

• The HCC Scientific Group Members: Amr Abdel Moety, Ashraf Omar, Gamal Esmat, Hussein Khaled, Fouad Aboutaleb, Khaled Abdelkarim, Mahmoud Elmetainy, Mary Gamal, Mohamed Shaker, Osama Elmalt, & Yousri Wasef. 

➡️ Abbreviations 

AFP (alphafetoprotein)

ALT(alanine aminotransferase)

AST(aspartate aminotransferase)

CBC (complete blood picture) BCLC (Barcelona Clinic Liver Cancer)   cHCC-CCA (combined  hepatocellularcarcinoma-cholangiocarcinoma).

CT (computed tomography) 

ECOG (eastern cooperative oncology group) 

FDG-PET Scan (fluorodeoxyglucose -positron emission tomography scan)

HbA1c(hemoglobin A1c or glycosylated hemoglobin)

HBV (hepatitis B virus) 

HCC (hepatocellular carcinoma) HCV (hepatitis virus)

iCCA (intrahepatic cholangiocarcinoma)

INR (international normalized ratio) MDT (multi disciplinary team) 

mRECIST(modified response evaluation criteria in solid tumors

MRI (magnetic resonance imaging) 

MWA (microwave ablation) 

NAFLD (non alcoholic fatty liver disease) 

PET (positron emission tomography) 

PT (prothrombin time)

PS (performance status) 

RECIST (response evaluation criteria in solid tumors) 

RFA (radiofrequency ablation) 

RT (radiotherapy) 

SBRT (stereotactic body radiotherapy) 

SRS (stereotactic radio surgery)

UNOS (united network for organ sharing)

TACE (trans arterial chemoemblisation) 

TARE (transarterial radio embolization) 

- Executive Summary

This guidance provides a data-supported approach to the primary prevention screening, diagnosis, staging, treatment and follow up of patients diagnosed with hepatocellular carcinoma (HCC).  

- Introduction

HCC is the most common tumour diagnosed in Egypt among males. It is also of the main causes of cancer related deaths. According to GLOBOCAN last census, the number of new cases of liver cancer in both sexes, all ages is about 28,000 new cases in the year 2020 representing 27.3% of male and 10.5% of female cancers. 

➡️ Purpose and scope

These guidelines are developed to improve the quality of care for HCC patients Via providing a uniform standard of care across the country to help in primary prevention, screening, early diagnosis for HCC and so less aggressive treatment options and improved clinical outcomes. 

These guidelines cover primary prevention, screening ,diagnosis, staging, treatment and follow-up of HCC.

 ➡️ Target audience

Clinicians who are involved in the care and treatment of patients with advanced HCC, including medical oncologists, radiation oncologists, clinical oncologist, hepatologists, gastroenterologists, surgeons, interventional radiologists, radiologists, pathologists, and palliative care specialists.

- Methodology

◾ A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation. 

◾ inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted: 

         - Selecting only evidence-based guidelines (guideline must include a report on systematic literature searches and explicit links between  individual recommendations and their supporting evidence).

         - Selecting only national and/or international guidelines. 

         - Specific range of dates for publication (using Guidelines published or updated 2015 and later). 

         - Selecting peer reviewed publications only.

         - Selecting guidelines written in English language.

         - Excluding guidelines written by a single author not on behalf of an organization in order to be valid and comprehensive, a guideline ideally requires multidisciplinary input. 

         - Excluding guidelines published without references as the panel needs to know whether a thorough literature review was conducted and whether current evidence was used in the preparation of the recommendations. 

◾ All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. the panel decided a cut-off point or rank the guidelines (any guideline scoring above 50% on the rigour dimension was retained) 

- Evidence assessment

According to WHO handbook for Guidelines we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO because these represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available through the on the following sites: 

◾  Table 1: Quality of evidence in GRADE  

◾  Table 2: Significance of the four levels of evidence  

- The strength of the recommendation

The strength of a recommendation communicates the importance of adherence to the recommendation:   

➡️ Strong recommendations  

With strong recommendations, the guideline communicates the message that the desirable effects of adherence to the recommendation outweigh the undesirable effects. This means that in most situations the recommendation can be adopted as policy. 

➡️ Conditional recommendations  

These are made when there is greater uncertainty about the four factors above or if local adaptation must account for a greater variety in values and preferences, or when resource use makes the intervention suitable for some, but not for other locations. This means that there is a need for substantial debate and involvement of stakeholders before this recommendation can be adopted as policy. 

➡️ When not to make recommendations. 

When there is lack of evidence on the effectiveness of an intervention, it may be appropriate not to make a recommendation. 

- Recommendations

1. Primary prevention of HCC.  

1a. Vaccination against hepatitis B reduces the risk of HCC and is recommended for all new-born and high-risk groups. 

Strong recommendation, Moderate  Quality Evidence(Observational study), (1)  

1b. Governmental health agencies should implement policies to prevent HCV/HBV transmission and encourage lifestyles that prevent obesity and metabolic syndrome.

Strong recommendation, High Quality Evidence(A systematic review ), (2)  

1c. In general, chronic liver diseases should be treated to avoid their progression. 

 Strong recommendation,Moderate  Quality Evidence(Narrative review), (3)  

  1d. In patients with chronic hepatitis, antiviral therapies leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are recommended, since they have been shown to prevent progression to cirrhosis and HCC development. 

Strong recommendation, Moderate Quality Evidence(Narrative  review), (3,4) 

 1e. Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy reduces but does not eliminate the risk of HCC development. 

 Strong recommendation, Moderate Quality Evidence(Observational cohort studies), (5,6)  

1f. Patients with HCV-associated cirrhosis and HCC treated with curative intent, maintain a high rate of HCC recurrence even after subsequent DAA therapy resulting in sustained viral response. close surveillance is advised in these patients. 

Strong recommendation, Moderate Quality Evidence(observational cohort study), (7)  

1g. Coffee consumption has been shown to decrease the risk of HCC in patients with chronic liver disease. In these patients, coffee consumption should be encouraged.

Strong recommendation, Moderate Quality Evidence (Prospective cohort studies), (8,9)  

2. Screening of HCC 

2a. Implementation of screening programs to identify at-risk candidate populations should be improved. Such programs are a public health goal, aiming to decrease HCC-related and overall liver-related deaths. 

Strong recommendation, High Quality Evidence(Randomized controlled Trial), (10)  

 2b. Screening for HCC is warranted in all patients with cirrhosis irrespective of aetiology as long as liver function and co-morbidities allow curative or palliative treatment .

 Strong recommendation, High Quality Evidence(Meta-analysis). (11) 

2c. Screening for HCC is warranted for all patients with chronic HBV, regardless of the fibrosis. 

Strong recommendation, High Quality Evidence(Systematic review), (12) 

2d. Screening for HCC is warranted in all patients with advanced fibrosis (F3 or F4) with HCV or NAFLD. 

 Strong recommendation, High Quality Evidence( Meat-analysis and Systematic review), (13,14)

2e. Screening of patients at risk of HCC should be carried out by abdominal Us with AFP every 4 months.   

Good practice statement

2f. Patients with liver nodule(s) < 1cm or 1-cm [LI- ADS 1or 2] on abdominal ultrasound should repeat short-interval ultrasound and AFP  after 3 months.

 Strong recommendation, Moderate Quality Evidence(Observational cohort study), (15)

2g. In at-risk patients with any suspicious lesion ≥ 1cm on ultrasound should undergo diagnostic  evaluation with multi-phasic contrast- enhanced CT or contrast-enhanced multi-phasic MRI.

Strong recommendation, High Quality Evidence( A systematic review and meta-analysis), (16)

3. Diagnosis and staging of HCC.  

3a. All patients with HCC should be carefully discussed and managed by an experienced multidisciplinary team(MDT) with the involvement of hepatologists , diagnostic radiologists, interventional radiologists, surgeons, transplant surgeons ,medical oncologists ,radiation oncologists, pathologists with hepatobiliary cancer expertise,clinical pharmacists nutritionists and palliative care specialists. 

Strong recommendation, Moderate Quality Evidence(Observational cohort study), (17)

 3b. The noninvasive diagnosis of HCC should be based on either multiphasic contrast-

 enhanced CT or dynamic contrast enhanced MRI for diagnosis and evaluation of tumor

 extent(number and size of nodules,vascular invasion,extra-hepatic spread),they should could

 be performed,interpreted, and reported through the CT/MRI Liver Imaging Reporting and Data

 System(CT/MRI LI-RADS).  

Strong recommendation, High Quality Evidence(Meta-analysis), (18)

3c. The diagnosis of HCC can be established if the typical vascular hallmarks of HCC (hypervascularity in the arterial phase with washout in the portal venous or delayed phase) are identified in a nodule of >1 cm diameter using one of the two contrast enhancing imaging techniques, either CT or MRI, in a cirrhotic patient.

Strong recommendation, High Quality Evidence(Systematic review and meta-analysis), (19)

3d. The optimal diagnostic method is core biopsy.Indicators for consideration of core needle biopsy include:        

• _.lesion> 1cm in cirrhotic patients  but does not meet imaging criteria for HCC in multi-phasic CT and MRI.

• .lesion meets imaging criteria for HCC but patients is not considered at high risk for HCC development(In non-cirrhotic patients).

•  .lesion meets imaging criteria for HCC but patient has elevated CA19-9 or CEA with   suspicion of iCCA or cHCC-C

Conditional recommendation, Moderate Quality Evidence(Narrative review), (20)

3e. Repeated bioptic sampling is recommended in cases of inconclusive histological or discordant findings, or in cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC.

Conditional recommendation, Moderate Quality Evidence(Observational cohort study), (21)

3f. Staging of HCC is important to determine outcome and planning of optimal therapy and includes assessment of tumour extent, AFP level, liver function, portal pressure and clinical performance status.

Strong recommendation, High Quality Evidence(Meta-analysis), (22)

3g. The Barcelona Clinic Liver Cancer(BCLC) is the commonly accepted staging system for prognostic prediction and treatment allocation.

Strong recommendation, Moderate Quality Evidence(network meta-analysis of observational studies), (23,24)

3h. Multiphasic contrast-enhanced CT or MRI of the abdomen, CT of the chest, and CT/MRI of the pelvis are also used in the evaluation of the HCC tumor burden to detect the presence of metastatic disease.

Conditional  recommendation, Moderate Quality Evidence (Narrative review), (25)

3i.Initial workup for patients with suspected HCC is a multidisciplinary evaluation including careful review of medical history to identify any potential chronic liver diseases, investigations of the etiologic origin of liver disease, an assessment of the presence of comorbidity, imaging studies to detect the presence of metastatic disease, and an evaluation of hepatic function, including a determination of whether portal hypertension is present.

Conditional Recommendation, Moderate Quality Evidence(Meta analysis), (26)

3j.Laboratory evaluation of patients with newly diagnosed HCC include tinvestigations to detect  Aetiology of liver disease: HBV (at least HBsAg and anti-HBc), HCV (at least antiHCV), iron status, autoimmune profile, HBA1C,  as indicated.

Good practice statement

3k. Initial Workup for patient with HCC include an initial assessment of hepatic function involves liver function testing including measurement of serum levels of bilirubin, AST, ALT, ALP, measurement of  PT expressed as INR, albumin, and platelet count (surrogate for portal hypertension). Other recommended tests include CBC, BUN, and creatinine to assess kidney function.

Conditional Recommendation, Moderate Quality Evidence(Observational cohort study), (27)

3l.Endoscopic assessment of any HCC patient: Upper GIT endoscopy is advised before

receiving systemic therapy or surgery.

Conditional Recommendation, Moderate Quality Evidence(observational cohort study), (28)

3m.FDG PET-scan is not recommended for early diagnosis of HCC because of the high rate of false negative cases  and  may be considered when there is an equivocal extrahepatic finding before liver transplant.

Strong Recommendation, High Quality Evidence(Meta-analysis), (29)

4.1.Management of early HCC 

4.1.a. Partial hepatectomy should be offered to HCC patients without advanced fibrosis and is the treatment of choice as long as an R0-resection can be carried out.

Strong recommendation, High Quality Evidence (Meta-analysis), (30) 

4.1.b. In the case of cirrhosis, surgical treatment is recommended for localized HCC with a single lesion and intact liver function (Child-Pugh A), and in the absence of clinically significant portal hypertension with the evaluation of the extent of partial hepatectomy, future liver remnant and patient performance status. 

Strong recommendation, High Quality Evidence (Meta-analysis and Cohort study), (30,31)

4.1.c For patients with chronic liver disease being considered for major resection, preoperative portal vein embolization should be considered. 

Strong recommendation, High Quality Evidence(Meta-analysis), (32)  

4.1.d. Patients meeting the UNOS criteria ([AFP level ≤1000 ng/mL and single lesion ≥2 cm and ≤5 cm, or 2 or 3 lesions ≥1 cm and ≤3 cm and no evidence of macro vascular involvement or extra-hepatic  disease] should be considered for liver transplantation.

Strong recommendation, High Quality Evidence, (33)   

4.1.e. Thermal ablation by RFA or MWA are recommended as an alternative for resection for a single nodule ≤ 3 cm, BCLC stage 0, and those early stages that are not candidates for resection. 

Strong recommendation, High Quality Evidence(Meta-analysis), (34)  

4.1.f. The number and diameter of lesions treated by RFA in one session should not exceed three lesions, 3 cm each. 

Conditional recommendation, Moderate Quality Evidence(Narrative review), (35)  

4.1.g. Unresectable lesions measuring up to 4 cm are recommended to be subject to local ablative therapy by radiofrequency ablation (RFA) or microwave ablation.

Strong recommendation, HighQuality Evidence (Systematic review), (36) 

4.1.h. Percutaneous ethanol injection is considered an option in some cases of very early HCC with tumor size up to 2 cm when thermal ablation is not technically feasible. 

Strong recommendation, High Quality Evidence(Systematic review), (37)  

4.1.i. EBRT (i.e. IMRT, SRS/SBRT) is recommended as a potential first line single option for patients with liver-confined HCC who are not candidates for curative options (surgery or thermal ablation) and for whom TACE is being considered.  

Strong recommendation, Moderate Quality Evidence (systematic review and meta-analysis of  
 observational studies), (38)  

4.1.j. Single lesions (4–6 cm) that are beyond local ablative therapy and are ineligible for surgical resection and transplantation could benefit from a combination of heat ablation and chemoembolization and/or radiotherapy. 

Strong recommendation, High Quality Evidence(Metaanalysis of RCTs), (39)  

4.1.k. TACE may be considered as an eligible option in intermediate HCC for bridging and down staging before liver transplantation and in case of non-feasibility or failure of other curative options in single lesions up to 8 cm.     

Conditional recommendation, Moderate Quality Evidence(Observational cohort study),(40)  

4.2.Management of Management of locally advanced/metastatic disease and palliative treatments HCC 

4.2.a. TACE is recommended for BCLC-B patients with Child score up to B7 and tumor burden less than 50 % of liver volume.   

Strong recommendation, High Quality Evidence(Systematic review), (41)  

  4.2.b. TACE should not be recommended for patients with decompensated liver disease (Child-Pugh score > 7), advanced liver and/or kidney dysfunction, main portal vein or its main branches invasion, extrahepatic spread, or tumor occupying>50 % of the liver size.

Strong recommendation, High Quality Evidence(Systematic review), (42)  

4.2.c. TACE should not be repeated after two consecutive sessions, with at least one month interval, and there is no response or there is tumor progression or decompensation of liver beyond Child-Pugh score B7). 

Conditional recommendation, Moderate Quality Evidence(observational cohort study (43)  

 4.2.d. Transarterial bland embolization may be used in same indications of TACE as A second choice if TACE is not feasible. 

Conditional recommendation, Moderate Quality Evidence(observational cohort study),(44)  

  4.2.e. Radiotherapy in HCC is recommended to be integrated in the treatment plan through expert MDT and should be carried out in well trained and equipped centers with image guided, stereotactic radiotherapy, and radiosurgery facilities. 

Strong recommendation, High Quality Evidence(systematic review ),(45)  

4.2.f. Radiotherapy could be implemented for unresectable or medically inoperable disease irrespective of the location (3D conformal RT, intensity-modulated RT [IMRT], or stereotactic body RT [SBRT]). 

  Strong recommendation, High Quality Evidence(systematic review), (45) 

4.2.g. To give radiotherapy, there should be no extrahepatic disease or it should be minimal and addressed in a comprehensive management plan. Most of the data on radiation for HCC liver tumors arise from patients with Child-Pugh A liver disease; safety data are limited for patients with Child-Pugh B or poorer liver function. Those with Child-Pugh B (max 7) cirrhosis can be safely treated, but they may require dose modifications and strict dose constraint adherence. 

Strong recommendation, Moderate Quality Evidence(observational cohort study), (46)   

4.2.h. Image-guided RT is strongly recommended to improve treatment accuracy and reduce treatment related toxicity. 

Strong recommendation, Moderate Quality Evidence(observational cohort study), (47)   

4.2.i. SBRT or SRS can be considered after ablation/ embolization techniques have failed or are contraindicated. 

Strong recommendation, High Quality Evidence(A systematic review  and meta analysis), (48)  

4.2.j. SBRT (typically 3–5 fractions) is recommended for patients with 1 to 3 tumors. And could be considered for larger lesions or more extensive disease, if there is sufficient uninvolved liver and liver radiation tolerance can be respected.  

Conditional recommendation, Moderate Quality Evidence (observational cohort study),(49)  

4.2.k. SBRT or SRS are recommended for compensated cirrhotic patients with HCC and portal vein thrombosis and when patients are ineligible for other modalities with building-up results. 

Conditional recommendation, Moderate Quality Evidence(observational  cohort study), (50)  

4.2.l. Palliative RT is indicated for symptomatic control and/or prevention of complications from metastatic lesions as bone or brain, and extensive liver tumor burden.  

 Strong recommendation, Moderate Quality Evidence(phase 2 trial), (51) 

4.2.m. The recommended doses of radiotherapy should be based on meeting normal organ constraints and underlying liver function as follows: 

◾  SBRT, SRS: 30–50 Gy (typically in 3–5 fractions) 

       Strong recommendation,

       Moderate Quality Evidence(a systematic review and meta-analysis of

       observational studies), (52) 

◾ Hypofractionation: 37.5–72 Gy in 10–15 fractions 

Strong recommendation,

Moderate Quality Evidence(observational cohort study), (53) 

◾ Conventional fractionation by IMRT: 50–66 Gy in 25–33 fractions  

Strong recommendation,
 High Quality Evidence (a systematic review and metaanalysis), (54)  

4.2.n. Systemic therapy should be offered to patients with preserved liver function(ChildTurcotte -Pugh A or well-selected Child-Turcotte-Pugh B cirrhosis),ECOG PS0-1,who have BCLC Stage C HCC,or BCLC Stage B HCC not amenable to or progressing after locoregional therapy. 

Strong recommendation, High Quality Evidence(a systematic  review and meta-analysis), (55)  

4.2.o. Sorafenib is the standard of care as first line for patients with advanced HCC and those with intermediate-stage (BCLC B) disease not eligible for, or progressing despite, locoregional therapies. It is recommended in patients with well-preserved liver function and ECOG PS 0-2. 

Strong recommendation, High Quality Evidence(a systematic review ),(56)  

4.2.p. Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed. It is recommended in patients with well- preserved liver function and ECOG PS 0-1. 

Strong recommendation, High Quality Evidence(randomized  controlled trial)(57)  

4.2.q. Patients with BCLC-Stage-D HCC should receive the best supportive care (BSC), including pain management, palliative radiotherapy for painful bone metastasis, nutrition optimization, and psychological support. 

Conditional recommendation, low Quality Evidence(review articles) (58,59) 

5.Follow up of HCC  

5a.Follow-up of patients who underwent radical treatments should consist of clinical evaluation, multiphasic, high-quality, cross-sectional imaging of the chest, abdomen, and pelvis(ie,CT or MRI) every 3 to 6 months for 2 years, then every 6 months and AFP should be measured every 3 to 6 months for 2 years, then every 6 months. Surveillance imaging and AFP should continue for at least 5 years and thereafter screening is dependent on HCC risk factors.

Conditional Recommendation, Moderate Quality Evidence(observational study), (60)

5b. Follow-up of patients with advanced stages of HCC treated with locoregional treatments or systemic therapies, periodic response assessment with cross-sectional imaging including chest, multiphase abdomen, pelvis  and serum level of  AFP (every 3 months)

Good practice statement

5c. Using the mRECIST Criteria in the assessment of progression and radiological response after HCC 100% Low management is recommended.

Conditional Recommendation, Moderate Quality Evidence(observational  study)(61)

- Clinical indicators for monitoring

▪️ For Screening 

   1-Abdominal and pelvic ultrasound. 

   2-Serum alpha -fetoprotein level. 

▪️ laboratory evaluation before each cycle of systemic treatment (monthly)     

    1- complete blood picture. 

    2-liver function tests (total serum bilirubin, serum albumin, SGPT and INR). 

    3-kideny function tests (serum creatinine, blood urea) 

➡️ Research gaps 

•  Systematic inclusion of cost-benefit analyses in clinical trial with collection of health economic analysis such as incremental cost effectiveness ratio in order to facilitate clinical decision-making. 

• Predictive biomarkers: response to specific systemic targeted therapies. 

•  Improve models for pre-clinical testing of novel drugs. 

• Search for tools to assess quality of life in clinical trials. 

•  Therapies to prevent dropouts in the waiting lists of liver transplantation and downstaging strategies. 

• Adjuvant therapy after curative treatments  

➡️Update of this guidline  

• This guidline will be updated whenever there is new evidence. 

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- Annexes

Assessment of clinical performance status BCLC staging and treatment strategy in 2022.