Hepatitis & Hepatocellular Carcinoma

Hepatitis and Hepatocellular Carcinoma

Prof. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA)

Consultant Medical Oncologist & Medical DirectorPrince Faisal Oncology Center, KFSHProfessor of Clinical MedicineQassim Medical University, Buraidah, Al-Qassim

6th most common cancer (2002 Globocan)626,000 new cases95% mort (598,000)3-5% SurvivalM:F ratio 1.3-3.6Increasing incid in some countries

Parkin DM Ca Cancer J Clin 2005;55:74HCC

AAIR(Number)

AAMR(Number)

Industrialized countries

Men 8.71(73,270)

8.07(68,992)

Women 2.86(33,680)

3.01(36,657)

Non industrialized

Men 17.43(325,108)

16.86(314,611)

Women 6.77(132,298)

6.57(128,305)

New Cases and MortalityNew Cases and Mortality

Bosch FX et al: Clin Liver Dis 2005; 9:191

Risk Factors for HCCRisk Factors for HCC

• Other risk factors– Alcohol intake– Aflatoxins*– Hemochromatosis– Other metabolic disorders

• α 1 antitrypsin deficiency• Porphyrias

– NASH– Diabetes

• Older age• Male gender• First degree relative with

HCC*

• Cirrhosis– A common denominator in

most cases– West 80-90% pts – KSA 50-60% pts– Africa 60-70% pts in

• HBV 50-55%• HCV 25-30%

Fattovich G: Int Hepat Conf; 2004:Paris Bosch FX et al: Clin Liver Dis 2005; 9:191

Nomenclature and Features of Nomenclature and Features of Hepatitis VirusesHepatitis Viruses

Type Virus particle Genome

A 27 nm 7.5 kb RNA, linear, ss, +

B 42 nm 3.2 kb DNA, circular, ss/ds

C 40-60 nm 9.4 kb RNA, linear, ss, +

D 35-37 nm 1.7 kb RNA, circular, ss,-

E 32-34 nm 7.6 kb RNA, linear, ss,+

Link Between HCC and HBV/HCVLink Between HCC and HBV/HCV

• Strong association in epidemiological studies– Parallelism between HBsAg carrier rate and

HCV infection and incidence of HCC– High rate of positivity of HBV/HCV in HCC

• 90% HCC pts in Taiwan + HBsAg• High rates of HCV in HCC pts in Japan

• 61.9% + HBV in KSA

• HBV/HCV molecules present in HCC

HCC Risk FactorsHCC Risk Factors

HCV HBV Alcohol OtherEurope 60-70% 10-15% 20% 10%

North Am 50-60% 20% 20% 10%

Japan 70% 10-20% 10% <10%

Asia & Africa

20% 70% 10% <10%*Aflatoxins co factor with HBV

Llovet JM et al: The Lancet 2003; 362:1907

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence

≥8% - High

2-7% - Intermediate

<2% - Low

450 million infected

Bosch FX et al: Clin Liver Dis 2005; 9:191

100 million infected

HCC in Saudi ArabiaHCC in Saudi Arabia

Site (Number)~

Qassim Riyadh Gizan Madina Riyadh Abha Al Baha

NHL (64)

11.53 8.50 NA NA 12.72 9.6 10.4

Liver (51)

9.17 14.48 18.72 9.4 5.50 11.0 6.5

Esophagus (45)

8.09 2.98 1.83 6.6 5.72 3.0 2.7

Stomach (44)

7.91 7.35 3.28 7.5 4.54 8.0 11.3

Skin (41)

7.38 2.75 12.51 8.8 3.97 14.6 15.2

Hodgk Dis(36)

6.47 3.90 NA NA 4.96 NA NA

Prostate (31)

5.57 6.20 4.20 3.2 1.87 2.3 4.2

Bladder (28)

5.03 4.82 8.58 5.1 3.52 9.4 7.5

Lip, oral cav (24)

4.31 NA 13.24 1.8 5.45 NA 4.5

Akhtar SS et al Ann Saudi Med 1997

1

1.9

2

2.8

3.2

3.4

3.9

4

5

5.9

6.6

10.5

15.2

0 2 4 6 8 10 12 14 16

Riyadh

Najran

Madinah

Qassim

Makkah

East

Jazan

Baha

Hail

Asir

North

Tabuk

Jouf

HCC ASR KSA (Males)- NCR -2000HCC ASR KSA (Males)- NCR -2000

Males Females

ASR 6.5 2.6

Mean Age 64 58

Hepatitis B Virus

Acute Hepatitis B Virus Infection with RecoveryTypical Serologic Course

Weeks after Exposure

Titer

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBsHBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Progression to Chronic Hepatitis B Virus InfectionTypical Serologic Course

Weeks after Exposure

Titer

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Outcome of Hepatitis B Virus Infectionby Age at Infection

Symptomatic Infection

Chronic Infection

Age at Infection

Ch

ron

ic I

nfe

ctio

n (

%)

Sym

pto

mat

ic I

nfe

ctio

n (

%)

Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults

0

20

40

60

80

100100

80

60

40

20

0

Lok A: NEJM 2002; 346:1683

Closed Circular DNA

Viral replication

Persists for life time? during Ch infection

Random integration into the host genome

Immortalized cells

Malignant phenotype

Genetic alteration

Inactivates p53, Free radical & superoxide prduction, induces genomic instability

Activates cellular oncogenes

Incidence of HCC during Follow Up Incidence of HCC during Follow Up of HBVof HBV

Yang HI: NEJM 2002; 347:168

Yang HI: NEJM 2002; 347:168

Cumulative incidence of HCC during Follow Up in Taiwan

Relative Risk compared to normal

HBsAg +ve only 9.6 (CI 6.0-15.2)

+HBeAg +ve also 60.2 (CI 35.5-102.1)

Genotypes B & C related to HCC

In HCV Cirrhosis annual HCC risk = 1-7%

Zhu AX: ASCO 2004

HCC & Chronic Viral Hepatitis HCC & Chronic Viral Hepatitis • Chronic HBV

– 9.6 X RR for HBsAg +– 60 X RR for HBsAg + & HBe Ag +– 0.3% annual risk in carriers– 4.2-6.6% risk in cirrhotic

• Chronic HCV– 17 X RR– Cirrhosis a prerequisite– 1-7% annual risk in cirrhotic

Donato et al: Int J Cancer 1998; 75:347

HCC What to do?HCC What to do?• You know the well defined risk factors

• Catch them young

• No definite screening program has been prospectively validated by RCT and not possible any more

• Most commonly used tools– AFP 6 monthly

– Ultrasound 6 monthly

HCC Screening AFPHCC Screening AFP• >400 ng/ml rare in benign disease• >1000 ng/ml suggestive of HCC• Positivity rate in established HCC

– 80-90% in Orient

– 60-70% in West

– App 80% in KSA

• Poor test for small tumors• ? Use of AFP L3 fraction• Other serological tests

– Desgammacarboxyprothrombin (DGCP) activity– Alpha-fucosidase

HCC USG AdvantagesHCC USG Advantages

• Sensitivity 81%

• Easily available

• Operator dependant

• Cheap

• New generation machines have better quality doppler

• Used in combination with AFP

HCC -Whom Shall We ScreenHCC -Whom Shall We Screen

Hep B Carriers Cirrhosis secondary toAsian males >40 yrs Chronic Hep C

Asian female >50 yrs Genetic hemochromatosis

Asian any age +ve F/His Alpha 1 antitrypsin def

Any pt with cirrhosis Alcoholic liver disease

Africans >20 yrs

Sherman M et al: Gastroenterol Clin N Am 2004; 33:671

Surveillance should continue even after anti viral therapy in cirrhotic!

Ryder SD: Gut 2003; 52(Siii):iii1

HCC Surveillance HCC Surveillance

• Lesions <1 cm reliable diagnosis difficult

• Close follow up required

• Nodules 1-2 cm in size false negative rate– 30-40%

• Helical CT and MRI (Contrast enhanced)– >80% accuracy

– MRI superior to CT

• PET no encouraging results yet

Liovet JM et al: The Lancet 2003; 362:1907

EASLD Surveillance StrategyEASLD Surveillance Strategy

Bruix J et al: J Hepatol 2001; 35:421

* HBsAg + pts

EASLD Diagnostic Criteria for HCCEASLD Diagnostic Criteria for HCC

1. Cytohistopathological diagnosis

2. >2 cm arterial hypervascular lesion detected by two coincident imaging techniques or

3. >2 cm arterial hypervascular lesion detected by one imaging technique with AFP >400 ng/ml (2 and 3 only in the setting of cirrhosis)

HCC Can We Prevent It?HCC Can We Prevent It?

• Well defined risk factors

• Poor treatment outcomes make it a must

• No established benefit of vigorous screening

• Increased understanding of hepatocarcinogenesis

• New drugs available

Craxi A et al: Clin Liver Dis 2005; 9:329

Education

Vigorous blood product screening

Aflatoxin prevention as in Sudan

Vaccination-Taiwan ExperienceVaccination-Taiwan Experience• Nation wide HBV vaccination program

– Initiated 1984

• HBsAg carrier state in children– Pre vaccination 10%– Post vaccination 10 yrs <1%

• Annual incidence of HCC (per 100,000) in children 6-14 yrs– 1981-86 0.70– 1986-90 0.57– 1990-94 0.36

Chang MH et al: NEJM 1997; 336:1855

HCC Presentation- SymptomsHCC Presentation- Symptoms

79.50%

69.50%

56%

50%

30%

0.00% 20.00% 40.00% 60.00% 80.00%

Anorexia

Jaundice

Malaise/Fever

Mass

Pain Up Abdo

Shobokshi O et al Hepatocellular Ca Technical Report 1409 AH

HCC TreatmentHCC Treatment

• Surgical resection

• Liver transplantation

• Local regional therapy

• Systemic therapy

• New targeted agents

Hayashi PH et al: Med Clin N Am 2005; 89:345

HCC Surgical resectionHCC Surgical resection

• Treatment of choice for non cirrhotic

• Single lesion preserved liver function

• 5 year surv 50-70%

• Tumour recurrence 60-100%– De-novo– True recurrences

• May be followed by transplantation

Hayashi PH et al: Med Clin N Am 2005; 89:345

HCC TransplantationHCC Transplantation

• Transplantation potentially curative therapy

• Milan Criteria generally followed– Solitary tumor <= 5 cm diameter– Multifocal

• <=3 nodules• <=3 cm

• No vascular invasion

Ryder SdD Gut 2003; 52 (Siii); iii1Burroughs A et al: Lancet Oncol 2004; 5:409

HCC Local Ablative TherapiesHCC Local Ablative Therapies• Chemical ablation

– Ethanol injection– Acetic acid injection– Hot saline injection

• Thermal ablation– Radiofrequency ablation– Microwave ablation– Laser ablation

• TACE

Lencioni R et al: Clin Liver Dis 2005; 9:301

HCC Percutaneous Ethanol InjectionHCC Percutaneous Ethanol Injection

• 1-10 ml ethanol through small bore needle– Real time observation possible (alcohol

hyperechoeic)

• Response rate 50-100%– Size is the determining factor

• Best response smaller lesions (<2 cm)

• Well tolerated• Multiple sessions needed• Selected candidates with <3 cm tumours

– 50% 5 yr survival– Almost similar to resection group

Hayashi PH et al: Med Clin N Am 2005; 89:345

HCC Radiofrequency AblationHCC Radiofrequency Ablation

• Thermal injury from electromagnetic energy by radio frequency probes

• Larger needle size

• USG guidance required

• Can be done– Percutaneously– Laparoscopically– Laparotomy

HCC RFAHCC RFA• More patient discomfort• Complication rate 8.9%

– Mortality 0.5%

• Advantages– Fewer sessions– Better response rates

• Survival similar to PEI (lesions <3 cms)• Local recurrence lesser• Becoming popular local ablative therapy• Need a RCT with resection

Hayashi PH et al: Med Clin N Am 2005; 89:345

HCC TACEHCC TACE• Most widely used therapy for uresectable HCC• Higher efficacy with larger tumours

– Not indicated in early stage disease

• Selective catherization of the feeding artery to the segment or subsegment

• Drug injected – No single drug or combination is better

– Doxorubicin, cisplatin commonly used

• Lipoidol used to increase chemotherapy contact time• Gelatin or polyvinly alcohol particles used to

embolise the vessel

HCC TACEHCC TACE

• Best candidates– Preserved liver function– Normal functional status

• Better for smaller tumours (<4-5cm)

• Meta-analysis confirms survival benefit of TACE compared to conservative therapy

Llovet JM et al: Hepatology 2003; 37: 429

HCC Systemic TherapyHCC Systemic Therapy• Few effective drugs

– Responses to Cisplatin+5FU therapy?

• As neoadjuvant?• Anti angiogenesis agents• EGFR inhibitors• Signal transduction inhibitors• Telomerase inhibitors• Immune therapy• Gene therapy• Nanoparticle therapy

Burroughs A et al: Lancet Oncol 2004; 5:409

Hayashi PH et al: Med Clin N Am 2005; 89:345

HCC TreatmentHCC TreatmentLarge HCC >5 cm Small HCC < 5cm

Resectable Resectable

Systemic chemo TACE

Unresectable

Local ablative therapy

TransplantationDefinitive resection

Unresectable

Leung T: ASCO 2005 Orlando Fl

HCC StagingHCC Staging

• UICC Staging• Tx-T4

• Nx-N1

• Mx-M1

• Vascular invasion T1-T3

• Single/multiple T1/T2,T3

HCC Staging OkudaHCC Staging OkudaTumor size

Ascites Bilirubin Albumin

>50%=+ <50%=-

+ or -

>3g/dl=+ <3g/dl=-

<3g/dl=+ >3g/dl=-

Stage I=all - Stage II=1 or 2 +

Stage III=3 or 4 +

HCC Radiologic Investig HCC Radiologic Investig USGUSG

• Vascular invasion sensitivity 17%

• Operator dependant

• 62 yrs M

• Rt hypoch pain

• Clinically ? Ac. Cholecystitis

• USG normal

• Rept CT scan & USG HCC

HCC DiagnosisHCC Diagnosis

• Biopsy

• USG/CT guided biopsy

• FNAC

• Special stains

HCC StagingHCC Staging

• UICC Staging• Tx-T4

• Nx-N1

• Mx-M1

• Vascular invasion T1-T3

• Single/multiple T1/T2,T3

HCC ManagementHCC Management

• Untreated 3/22 alive at 3 yrs even with small tumours

• Median survival 8.3 months (Stage I)

• Surgical

• Chemotherapy

• Radiation therapy

• Biological response modifiers

HCC ResectionHCC Resection

• 30-50% Survival

• <2 cms 85% 5 yr survival

• 4 cms 60% 5 yr survival

• 80% without cirrhosis

• 35% with cirrhosis

HCC Etiology HBV/AflatoxinsHCC Etiology HBV/Aflatoxins

• High level and prevalence of exposure to aflatoxins in West Africa, Mozambique, some regios of China

• High prevalence of 249ser p53 mutation in these countries

• HCC from low aflatoxin exposure countries low prevalence of mutation

Montesano R et al Hepatocellular Ca JNCI 1997;1844

HCC Etiology HBV/AflatoxinsHCC Etiology HBV/Aflatoxins

• p53 mutaion occurs early

• Perinatal aflatoxin exposure

• HBV infection alters aflatoxin metabolism

• ?Recurrent liver cell proliferation in HBV carriers favors selective clonal development of aflatoxin mutated cells

Montesano R et al JNCI 1997;89:1844