Egyptain HCC Guidelines

The Egyptian Guidelines for Management of Hepatocellular Carcinoma

by

Egyptian Society of Liver Cancer

Index

• Figure (1): ESLC Diagnostic Algorithm For Hepatocellular Carcinoma.

• Figure (2): ESLC Therapeutic Algorithm for Single HCC.

• Figure (3): ESLC Therapeutic Algorithm for Multiple HCC.

Introduction

Egypt is considered nowadays as one of the hot spots in the international map of Hepatocellular Carcinoma. Obviously there are several local factors contributing in presenting HCC that differ from the internationally known factors for the same disease. First of all, hepatitis C virus infection is a major risk factor in development of HCC, but genotype 4 is a predominant endemic and unique etiology among Egyptian patients. Secondly, the socioeconomic status of the patients and the absence of uniform health insurance that cover all population, could play a majorrole in the different presentation of the disease rather than that in Europe, Asia and western countries. Thus, those patients could presentwith advanced disease due to the shortage of complementary high quality diagnostic tools such as contrast enhanced ultrasound and the recent generations of magnetic resonant machines that cover the required standard uniform level of care among all Egyptians in every governorate.On the other side of the story, cadaveric liver transplantationis not available.

In respect to the previous mentioned facts, starting by the different etiology passing through the different socioeconomic circumstances, and ending by the unavailability of cadaveric transplantation. The ESLC decided to focus all their efforts during the last annual scientific meetingthat has been held on the 1st and 2nd of June 2011, to finalize the pilot broad lines for management of hepatocellular carcinoma, aiming to find a clue for the Egyptian HCC patients. Where most of experts with different specialties in that field all over the country, have been invited to discuss the new guidelines taking into consideration basically the international guidelines (level I evidence based), and in parallel considering as well the local factors in Egypt, in addition to their own experience (level III, expert opinion) in those points which could not be applicable in Egypt, provided that it is based on reliable international publications.Confirmation and collecting these points are done using live voting system, while Finalization and drafting of the previously accepted guidelines has been accomplished by another sub-committee composed of 29 experts of different specialties on the 15th and 16th of September 2011. The final draft has been completely endorsed by the ESLC to be applied for the Egyptian HCC patients.

ESLC Board

List of Abbreviations

Prevention:

Hepatocellular Carcinoma (HCC) is a preventable disease.Considering this, we have to take into account all the 3 forms of prevention:

• Primary Prevention

1. Prevention of Chronic HBV and HCV infections by:

-Safe injection practices. These are based on education of medical and para-medical personnel about safe practice and proper disposal of needle and infusion techniques, to reduce the risk of needle-stick injuries.

-Screening of donated blood for the presence of hepatitis viruses.

-Passive immunization. Passive immunization with hyperimmune γ-globulin preparations is useful in preventing hepatitis virus infections but is expensive and its effect is of limited duration.

-Antiviral therapeutic agents. Currently used agents have limited efficacy in the sustained eradication of HBV and HCV in patients chronically infected with these viruses. Nevertheless, treatment with interferon-α does appear to prevent the development of HCV-induced hepatocellular carcinoma (see tertiary prevention).

-Immunization against HBV.The introduction of HBV vaccine into the Expanded Programme of Immunization in many countries and the effect that this has already had in reducing the viral carriage rate and the occurrence of hepatocellular carcinoma is undoubtedly the most exciting development in the prevention of hepatocellular carcinoma.

1. Avoid Aflatoxin B1 exposure by education of and financial assistance to subsistence farmers to allow them to improve methods of storing staple crops.

1. Prevention ofdietary iron overload by westernization of the cooking habits and tools.

• Secondary prevention

Venesection for cases with high iron overload.

• Tertiary Prevention

-Prevention of progression of the cirrhosis to hepatocellular carcinoma is done by treating the hepatitis B and C virus infections with interferon-α and/ or oral antiviral therapy.

-Preventing hepatocellular carcinoma caused by alcoholic cirrhosis by quitting of or avoiding excessive alcohol intake.

-Prevention of Non alcoholic steato-hepatitis, in obesity and Diabetes mellitus are the major predisposing factors of non viral chronic necroinflammatory liver disease. Consequently, tight control of serum blood sugar by antidiabetic medications, changing diet habits and weight reduction are main preventive measures against development of HCC.

Screening:

• Screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival.
• Screening for HCC should be performed for all high risk groups every 4 months with both:

1. Abdominal U/S aiming at early detection of HFL.
2. AFP aiming at early detection of rising titer or serum level is ≥ 200 ng/dl.

• High risk groups for HCC are:

A)All cirrhotic patients:

-HBV.

-HCV.

-NASH.

-Alcoholic.

-Haemochromatosis.

B)Non cirrhotic patients:

-HBV infection (carriers).

Diagnosis:

• The diagnosis of Hepatocellular Carcinoma is made as follow:

-High risk patient with HFL and either serum AFP is ≥ 200 ng/ml, or triphasic CT-scan abdomen shows typical criteria for HCCthen, it has to be diagnosed as HCC.(NB: Radiological criteria of HCC is in the form of early enhancement during arterial phase followed by rapid washout of contrast in delayed phase)

-High risk patient with HFL1cm, AFP < 200 ng/ml, then follow up every 2 months by abdominal U/S and serum AFP is recommended.If the lesion increases in size then, reassess with triphasic CT-scan abdomen.

-High risk patient with HFL ≥ 1cm, AFP has normal level or < 200 ng/ml and triphasic CT-scan abdomen shows atypical criteria for HCC then,a dynamic contrast MRI (with magnet strength≥1.5 tesla) is recommended.If MRI is not available or its result is not satisfactorythen targeted liver biopsyis recommended.

-High risk patient with serumAFP ≥200 ng/ml and no HFL could be detected neither by abdominal U/S nor trisphasic CT-scan abdomenthen, a dynamic MRI study (≥1.5 tesla) is recommended.

• The recommended Workup for HCC patient at time of diagnosis is:

-Full History (concerning the risk factor, occupation, exposure to toxins, chemical …etc).

-Physical Examination.

-CBC.

-Bleeding profile (PT, INR and PTT).

-Liver function tests and LDH.

-Kidney function tests.

-AFP.

-Etiologies of liver cirrhosis: (HBsAg, HBcAb, HCV-Ab).

-ECG.

-Triphasicspiral CT-scan abdomen or MRI ≥1.5 tesla whenever indicated.

• Indications forHCC metastatic workup are:

1. Clinical suspicion.
2. Prior to transplant.

• Screening for HCC metastasis is performed with:

-Chest/Pelvis CT with contrast.

-Bone scan on clinical suspicion or in symptomatic patients.

Staging:

It should include the proper assessment of differentviews covering; the patient clinical state, liver state, tumor size, number, site, vascular invasion and extrahepatic disease.

• ECOG performance status is used for evaluation of the patient's general condition.
• Child Pugh classificationis used for evaluation of the liver condition in cirrhotic patients.
• The Barcelona Clinic of Liver Cancer (BCLC) stagingis used for assessment of the tumor stage.
• The Cancer of the Liver Italian Programme (CLIP) scoreisa good prognosticator for survival and post-therapeutic response.

Surgical Resection:

• Patient who is fit for surgical resection should fulfill the following conditions:

-Child Pugh score <6 (Child A).

-Good performance status.

-Site is anatomically accessible(cases with subcapsular HCC are good candidates for surgical resection while deep lesions should be assessed first for the possibility of ablative therapies).

-Serum bilirubin 1.5 mg/dl.

-Localized HCC.

-No vascular invasion.

-Absence of extrahepatic spread (EHS).

-Absence of portal hypertension.Inspite of this, portal hypertension is not an absolute contraindication in the following situations (peripheral or exophytic lesions not suitable for local ablative treatment).

N.B: Criteria predicting portal hypertension are:

•Platelets count < 100,000 /mm3.

•Splenomegaly.

•Upper GIT endoscopyshowing either esophageal varices or signs of portal hypertensive gastropathy.

•Hepatic Venous Wedge Pressure (HVWP > 10 mmHg).

• Large HCC lesion is not a contraindication for liver resection provided an adequate residual volume of the cirrhotic liver after proper metastatic workup.

• N.B: operative theatres for liver surgery should be fully equipped with all facilities and equipments required especially operative ultrasound machine and capability of operative ablative therapy.

Liver transplantation:

• Milan Criteria is the gold standard for the selection of HCC patients for Liver transplantation (refer to page ….).

• Liver transplantation will be beneficial for recurrent HCC within Milan criteria after liver resection with the following criteria:

-No micro-vascular invasion.

-Well differentiated HCC.

-Acceptable AFP1000 ng/ml.

• UCSF criteria is the only validated extended criteria for Liver transplantation in HCC patients, taking into consideration that LDLT versus DDLT would impact decision making in Transplantation of HCC patients with extended criteria beyond Milan (refer to page ….).

• In bridging or downstaging of Hepatocellular Carcinoma either by surgical resection or locoregional therapy, liver transplantation could be done if:

-Serum AFP is < 1000 ng/ml.

-Adequate radiological response (Partial and complete responders) according to modified RECISTcriteria after locoregional therapy.

-Absence of disease progression during time period of 3 months.

• Local recurrence of HCC after liver transplantation may be treated withsurgery if it is resectable, or with loco-regional therapy if it is unresectable. While Sorafenib is the only available systemic therapy indicated in distant recurrent HCC.

Locoregional Therapy:

• HCC ≤ 4 cm, away from main bile ducts or intestinal loops, without vascular invasion or extrahepatic spread in Child-Pugh A or B patients neither candidate for surgery nor ready for liver transplantation, are candidates for Radiofrequency (RFA) or Microwave ablation.

• HCC ≤ 4 cm close to a great vessel, without vascular invasion or extrahepatic spread in Child-Pugh A or B patients neither candidate for surgery nor ready for liver transplantation, are candidates for Microwave ablation.

• RFA and Microwave ablation are contraindicated in lesions located in close contact with main bile ducts or intestinal loops. So, the best clue for these patients with Child Pugh Class A or B, neither fit for resection nor transplantation, is Percutanous Ethanol Injection (PEI) in lesions 3 cm orcombined Transarterial Chemoembolization (TACE) + PEI for lesions 3 – 6 cm. Also intra operative RFA could be an alternative for patient who is fit for surgery with single HCC ≤ 4cm close to intestinal loops.

• HCC measuring 4 – 6 cm, away from main bile ducts or intestinal loops without vascular invasion or extra-hepatic spread in Child A or B patient neither candidate for surgery nor ready for transplantation, are candidates for combined therapy of Heat ablation (with RFA or Microwave ablation) + TACE.

• HCC measuring ≥ 6 cm or multifocal lesions, without vascular invasion or extra-hepatic spread in Child A and early B and not candidate for surgical management, couldbe treated withTACE. Addition of Sorafenib is optional, to act against the rising serum level of VEGF which occur especially during the first week after embolization.

• Ablation therapy could be performed as a potentially curative modality for up to 3 lesions, however, cases with more than 3 lesions are not an absolute contraindication for ablation and should be discussed on a case by case basis.

• Single or multifocal HCC with portal vein invasion in Child Pugh Class A or early B patient are candidates for Sorafenib. Furthermore, in respect to the rising promising data coming to support the use of Selective Internal Radiotherapy (SIRT) with Y-90 in advanced HCC especially in case of portal vein thrombosis. Radioembolization with Y-90 could be recommended as a second line of treatment for those patients in the following situations:

-Progressive disease inspite of full dose Sorafenib.

-Patient who can’t tolerate the adverse events of Sorafenib.

Systemic treatment:

• Sorafenib is the standard systemic therapy indicated for treatment of hepatocellular carcinoma in the following conditions:

-Extrahepatic spread (such as lymph node, lung or suprarenal metastasis).

-Vascular invasion (such as malignant portal vein or hepatic vein invasion).

-In patients withpost-transarterial chemoembolization (TACE) progressive disease.

• HCC patient who is candidate for Sorafenib should have Child A liver cirrhosis or early B(score≤7), good performance status, and serum bilirubin ≤ 2 mg/dl.
• The standard daily oral dose of Sorafenib is 800 mg/day (divided into two doses per day) one hour before meals or two hours after meals. In case of treatment related adverse events temporary interruption and/or dose reduction of sorafenib therapy may be required. When dose reduction is necessary, the dose may be reduced to 400 mg once daily, and if additional dose reduction is required, sorafenib may be reduced to 200mgdaily.
• N.B: If serum bilirubin is ≥1.5mg/dl ,we start with half dose of Sorafenib.
• Clinical follow up of patients on Sorafenib should be performed twice monthly after beginning of treatment then monthly on a regular basis.

While assessment of radiological response with modified RECIST criteria is accepted with triphasic spiral CT-scan or MRI (≥1.5 tesla) every three months.

• Addition of external beam radiotherapy is amenable in case of bone metastasis together with Sorafenib

• Finally, we are aware of the plethora of targeted therapies that are in progress in phase II and III clinical trials. Therefore in case of Sorafenib failure in patients who are still maintaining child score A and good performance status, they could be included into clinical trials.

Best Supportive Care:

• It is the only line of treatment indicated for end stage HCC which is defined by; poor performance score or child C liver cirrhosis who are not eligible for transplantation.
• Best supportive care should cover the following states:

1. Treatment of portal hypertension.
2. Nutritional management.
3. Pain management.
4. Psychological management.
5. Control of ascites.

Post-therapeutic monitoring for HCC patients:

1. Clinical:

Reassessment of the patient’s general condition and his performance status is mandatory.

1. Serological:
2. AFP (if elevated at baseline).
3. CBC.
4. LFTs (especially S. bilirubin).
5. KFTs (especially S. uric acid).
6. PT and INR
7. Radiological:

It is recommended to perform tri-phasic CT-scan abdomen one month after initial treatment, then every 3 monthsduring the first year after therapy.

Then every 6 months if the patient does not develop recurrence or disease progression ,meanwhile he should enter in the screening program by abdominal U/S and serum AFP / 4 months ,aiming early detection of new HCC.

Invited Experts

Attended Experts

Acknowledgement

This Report would not have been possible without the essential organizing and gracious scientific effort of Dr Amr El Fouly (Lecturer of Hepatology - Atomic Energy Authority) and Dr Omar Abdelrhman (Assistant lecturer of Clinical Oncology – Ain Shams University).

Milan Criteria

UCSF Criteria

Child Pugh Classification: