ESLC
2011
The Egyptian Guidelines
for Management of Hepatocellular
Carcinoma
by
Egyptian Society of Liver Cancer
First Edition
2011
ESLC 2011
Egyptian Guidelines for HCC
Index
Page
Introduction
……………………………………………
3
List of Abbreviations
……………………………………………
4
Prevention
……………………………………………
Screening
……………………………………………
Diagnosis
……………………………………………
Staging
……………………………………………
Surgical Resection
……………………………………………
Loco-regional Therapy
……………………………………………
Systemic Therapy
Best Supportive Care
……………………………………………
Monitoring after Therapy
……………………………………………
Drafting Committee
……………………………………………
List of Tables:
-
ECOG performance Status.
-
Child Pugh Classification.
-
The Cancer of the Liver Italian Programme (CLIP) score.
-
The Barcelona Clinic of Liver Cancer (BCLC) Staging system.
Legend of Figures:



Figure (1): ESLC Diagnostic Algorithm For Hepatocellular Carcinoma.
16
Figure (2): ESLC Therapeutic Algorithm for Single HCC.
17
Figure (3): ESLC Therapeutic Algorithm for Multiple HCC.
18
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ESLC 2011
Egyptian Guidelines for 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 major role in the different presentation
of the disease rather than that in Europe, Asia and western countries. Thus, those patients
could present with 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
transplantation is 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 meeting that 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
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ESLC 2011
Egyptian Guidelines for HCC
List of Abbreviations
AFP
Alpha Fetoprotein
BCLC
Barcelona Clinic of Liver Cancer
BSC
Best Supportive Care
CBC
Complete Blood Picture
CLIP
Cancer of the Liver Italian Programme
CT-scan
Computerized Tomography
DDLT
Deceased Donor Liver Transplantation
EHS
Extra-Hepatic Spread
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HFL
Hepatic Focal Lesion
HVWP
Hepatic Vein Wedge Pressure
INR
International Normalization Ratio
KFTs
Kidney Function Tests
LDLT
Living Donor Liver Transplantation
LFTs
Liver Function Tests
MRI
Magnetic Resonance Image
NASH
Non Alcoholic Steato-Hepatitis
PEI
Percutaneous Ethanol Injection
PT
Prothrombin Time
RECIST
Response Evaluation Criteria In Solid Tumors
RFA
Radiofrequency Ablation
SIRT
Selective Internal Radiotherapy
TACE
Transarterial Chemoembolization
U/S
Ultrasound
UCSF
University of California, San Francisco
ULN
Upper Limits of Normal
VEGF
Vascular Endothelia Growth Factor
Y-90
Yttrium-90
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ESLC 2011
Egyptian Guidelines for HCC
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 needlestick injuries.
- Screening of donated blood for the presence of hepatitis viruses.
- Passive immunization. Passive immunization with hyperimmune γglobulin 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 HCVinduced 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.
2. Avoid Aflatoxin B1 exposure by education of and financial
assistance to subsistence farmers to allow them to improve
methods of storing staple crops.
3. Prevention of dietary 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.
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Egyptian Guidelines for HCC
ESLC 2011
- 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 HCC then,
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)
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ESLC 2011
Egyptian Guidelines for HCC
- High risk patient with HFL < 1cm, 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
satisfactory then targeted liver biopsy is recommended.
- High risk patient with serum AFP ≥ 200 ng/ml and no HFL could
be detected neither by abdominal U/S nor trisphasic CT-scan
abdomen then, 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.
- Triphasic spiral CT-scan abdomen or MRI ≥1.5 tesla whenever
indicated.
 Indications for HCC 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.
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ESLC 2011
Egyptian Guidelines for HCC
Staging:
It should include the proper assessment of different views 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 classification is used for evaluation of the liver condition
in cirrhotic patients.
 The Barcelona Clinic of Liver Cancer (BCLC) staging is used for
assessment of the tumor stage.
 The Cancer of the Liver Italian Programme (CLIP) score is a 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:
3
• Platelets count < 100,000 /mm .
• Splenomegaly.
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ESLC 2011
Egyptian Guidelines for HCC
•
•
Upper GIT endoscopy showing 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 AFP < 1000 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 RECIST criteria after locoregional therapy.
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ESLC 2011
Egyptian Guidelines for HCC
- Absence of disease progression during time period of 3 months.
 Local recurrence of HCC after liver transplantation may be treated
with surgery 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 or combined 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.
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ESLC 2011
Egyptian Guidelines for HCC
 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 with TACE.
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 with post-transarterial chemoembolization (TACE)
progressive disease.
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ESLC 2011
Egyptian Guidelines for HCC
 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 200mg daily.
o 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.
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ESLC 2011
Egyptian Guidelines for HCC
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.
2. Serological:
 AFP (if elevated at baseline).
 CBC.
 LFTs (especially S. bilirubin).
 KFTs (especially S. uric acid).
 PT and INR
3. Radiological:
It is recommended to perform tri-phasic CT-scan abdomen one month after
initial treatment, then every 3 months during 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.
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ESLC 2011
Egyptian Guidelines for HCC
Invited Experts
Abdul Rahman El Zayadi
Gamal Shehaa
Monier Zaki
Adel Hosni
Hamdy Abd El Azim
Mostafa El Shazly
Ahmed El Dorry
Hany Khattab
Nabil El Kaady
Ahmed Samy
Hussien Khalid
Refaat Refaat Kamel
Amr Helmy
Ibrahim Marwan
Sameh Abd El Wahab
Ashraf Omar
Imam Waked
Samir Shehata
Ayman Yousry
Mahmoud El Meteini
Seham Abd El Rehim
Ebtisam Saad El Din
Mohamed Abd El Wahab
Serag Zakaria
El Saeid Ibrahim
Mohamed Ali Ezz El Arab Talal Amer
Emad Hamada
Mohamed Kamal Shaker
Tarek Ibrahim
Fouad Abo Taleb
Mohamed Shaker Gazy
Waheed Doss
Gamal Essmat
Mohamed Tawfeek
Yousry Goda
Attended Experts
Abdul Rahman El Zayadi
Fouad Abo Taleb
Mohamed Tawfeek
Adel Hosni
Gamal Essmat
Mostafa El Shazly
Ahmed El Dorry
Hany Khattab
Nabil El Kady
Ahmed Samy
Ibrahim Marwan
Sameh Abd El Wahab
Amr Helmy
Imam Waked
Serag Zakaria
Ashraf Omar
Mahmoud El Meteini
Talal Amer
Ayman Yousry
Mohamed Abd El Wahab
Tarek Ibrahim
Ebtisam Saad El Din
Mohamed Ali Ezz El Arab
Waheed Doss
El Saeid Ibrahim
Mohamed Kamal Shaker
Yousry Goda
Emad Hamada
Mohamed Shaker Ghazy
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ESLC 2011
Egyptian Guidelines for HCC
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).
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ESLC 2011
Egyptian Guidelines for HCC
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Egyptian Guidelines for HCC
ESLC 2011
Milan Criteria
Milan criteria is defined as (a single HCC < 5 cm or multiple HCC not
more than 3 lesions and the largest is measuring ≤ 3 cm).
UCSF Criteria
The UCSF criteria for liver transplantation in patients with HCC are
defined (Single lesion ≤ 6.5 cm or multiple lesions not more than 3
and the largest is ≤ 4.5 cm in diameter and the cumulative diameter
of all lesions is ≤ 8 cm).
ECOG Performance Status:
Grade
Characteristics
0
Asymptomatic and fully active
1
3
Symptomatic; fully ambulatory; restricted in physically strenuous activity
Symptomatic; ambulatory; capable of self-care; >50% of waking hours
are spent out of bed
Symptomatic; limited self-care; spends >50% of time in bed
4
Completely disabled; no self-care; bedridden
2
Child Pugh Classification:
Points
Criteria
1
2
3
Serum bilirubin (mg/dL)
<2
2-3
>3
Serum albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
Ascites
None
Slight or easily
controlled
Moderate or
poorly
controlled
Encephalopathy
None
Grade 1-2
Grade 3-4
Prothrombin time
Prothrombin concentration
(INR)
< 4 sec
> 60 %
< 1.7
4-6 sec
40-60 %
1.7-2.3
> 6 sec
< 60%
> 2.3
Note: Child-Pugh class A: 5-6 points; Child-Pugh class B: 7-9 points, Child-Pugh class C:
10-15 points.
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ESLC 2011
Egyptian Guidelines for HCC
The Cancer of the Liver Italian Programme (CLIP) score:
Variable
0
1
2
Child-Pugh
A
B
C
Tumor
morphology
Uninodular and
extension < 50%
Multinodular and
extension < 50%
Massive or extension
> 50%
AFP
< 400
> 400
PVT
No
Yes
Early stage = (0 point); Intermediate stage = (1-3 points); Advanced stage = (4-6).
The Barcelona Clinic of Liver Cancer (BCLC) Staging System:
BCLC
stage
PST
Tumor stage
Okuda
stage
Liver Function
Early Stage HCC
No portal hypertension and
normal bilirubin
Portal hypertension and normal
bilirubin
Portal hypertension and abnormal
bilirubin
A1
0
Single, <5 cm
I
A2
0
Single, <5 cm
I
A3
0
Single, <5 cm
I
A4
0
3 tumors
<3cm
I-II
Child-Pugh A–B
I-II
Child-Pugh A–B
I-II
Child-Pugh A–B
III
Child-Pugh C
Intermediate HCC
Stage B
0
Large
multinodular
Advanced HCC
Stage C
1-2
Vascular
invasion or
extrahepatic
spread
End stage HCC
Stage D
3-4
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