egyptain hcc guidelines - prof. gamal esmat · web vieweslc 2011 first edition 2011 the egyptian...

First Edition2011

The Egyptian Guidelines for Management of

Hepatocellular Carcinomaby

Egyptian Society of Liver Cancer

ESLC 2011

ESLC 2011 Egyptian Guidelines for HCC

IndexPage

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

2


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

3


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 NormalVEGF Vascular Endothelia Growth FactorY-90 Yttrium-90

4


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.

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.

5


- 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)

6


- 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.

7


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:

• Platelets count < 100,000 /mm3.• Splenomegaly.• Upper GIT endoscopy showing either esophageal varices

or signs of portal hypertensive gastropathy.

8


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

9


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.

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.

10


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.

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.

11


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.4. Psychological management.5. Control of ascites.

Post-therapeutic monitoring for HCC patients:12


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.

13


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 ExpertsAbdul 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

14


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).

15


Milan CriteriaMilan 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 CriteriaThe 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 active1 Symptomatic; fully ambulatory; restricted in physically strenuous activity

2 Symptomatic; ambulatory; capable of self-care; >50% of waking hours are spent out of bed

3 Symptomatic; limited self-care; spends >50% of time in bed4 Completely disabled; no self-care; bedridden

Child Pugh Classification:

CriteriaPoints

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 timeProthrombin concentration

(INR)

< 4 sec> 60 %< 1.7

4-6 sec40-60 %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.

16


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

A1 0 Single, <5 cm I No portal hypertension and normal bilirubin

A2 0 Single, <5 cm I Portal hypertension and normal bilirubin

A3 0 Single, <5 cm I Portal hypertension and abnormal bilirubin

A4 0 3 tumors <3cm I-II Child-Pugh A–B

Intermediate HCC

Stage B 0 Large multinodular I-II Child-Pugh A–B

Advanced HCC

Stage C 1-2

Vascular invasion or extrahepatic

spread

I-II Child-Pugh A–B

End stage HCC

Stage D 3-4 III Child-Pugh C

17

egyptain hcc guidelines - prof. gamal esmat · web vieweslc 2011 first edition 2011 the egyptian...

Documents