Prof. Massimo ColomboCo-Chairman Department of Medicine, Head Division of GastroenterologyFondazione IRCCS Policlinico, Mangiagalli e Regina ElenaUniversità degli Studi di MilanoMilano

Paris Hepatitis Conference

Paris, 19th-20th January 2009

Screening and diagnosis of hepatocellular carcinoma

Increasing Incidence of Early Stage HCC in the Referral CentersThe Experience in Japan

Diagnostic period Stage I (n=274) Stage II (n=448) CTP A (n=726)

1968-1980 (n=151) 2 (1.3%) 6 (4.0%) 37 (24.5%)

1981-1990 (n=409) 32 (7.8%) 85 (20.8%) 138 (33.8%)

1991-2000 (n=757) 155 (20.5%) 249 (32.9%) 351 (46.4%)

2001-2004 (n=324) 85 (26.3%) 108 (33.3%) 200 (61.7%)

Toyoda H et al, Clin Gastroenterol Hepatol 2006;4:1170-1176

Ogaki Municipal Hospital, Japan. Data-base: 1968-2004. 1641 patients with a HCC

Curative treatments in 1067 (65%)

Groups of Patients for whom Surveillance Is Recommended

1EASL Conference, Bruix et al J Hepatol 2001;35:421-430 ; 2AASLD Practice Guidelines, Bruix & Sherman Hepatology 2005;42:1208-12363JSH Clinical Practice Guidelines for HCC, Makuuchi et al Hepatol Res 2008;38:37-51

TARGET POPULATION

Guidelines Chronic hepatitis B or C Cirrhosis

1EASL HBV: not specified

HCV: histological transition to cirrhosis

Child-Pugh A & B

Child-Pugh C if LT available

2AASLD HBV: ALT + DNA +

Age cut-offs for ethnic groups

All etiologies

3JSH Increasing risk: sex, age, alcohol Very high risk: HBV/HCV

Are Surveillance Programs Improved by Patients Stratification by Clinical and Histological Scores?

Study Patients Predictors High risk group Low risk group

Ganne-Carrié 19961 Cirrhosis, mixed Age > 50 yr HCC = 24% at 3 yr HCC = 0 at 3 yr

(France) etiology Male sex (LLCD+ = 72%)

(151 training, Large varices

Screening spared in 44% patients

0 HCC missed

49 validation) Pro-time < 70%

AFP ≥ 15 ng

HCV-Ab

Velasquez 20032 Cirrhosis, mixed Age ≥ 55 yr HCC = 30.1% at 4 yr HCC = 2.3% at 4 yr

(Spain) etiology (n=463) HCV-Ab

Pro-time ≤ 75% Screening spared in 58% patients

10% HCC missedPlatelets ≤ 75,000

1 Hepatology 1996;23:1112-1118; 2 Hepatology 2003;37:520-527

Studies Comparing the Diagnostic Accuracy and Outcome of Surveillance with Different Screening Intervals

Study Design Intervals mo. Screening outcome

Santagostino 20021 (Milan, Italy)

Multicenter comparative

559 hemophiliacs HCV+

6 vs 12 No differences in detection of early

cancer

Jan 20062

(Taipei, TW)

Community-based RCT

4,180 with mixed risks

6 vs 12 No differences in early cancer

detection and mortality rates

Trinchet 20073

(Bondi, F)

Multicenter RCT

1,190 cirrhotics HCV/Etoh

3 vs 6 No differences in detection. More

false positives in the 3 month arm

1 Blood 2003;102:78-82; 2 J Hepatol 2006;44 Suppl 2:S4; 3 ILCA Proceedings Barcelona 5-7 October 2007, 11

Radiological Diagnosis of Hepatocellular Carcinoma in Patients With CirrhosisEASL/AASLD Guidelines

Imaging techniques contrast-enhanced US, contrast-enhanced spiral CTand gadolinium-enhanced MRI

1-2 cm node two imaging techniques showing hyperenhanced node in the arterial phase and hypoenhanced node in the portal phase (wash-out)

> 2 cm node one imaging technique

EASL, AASLD & JSH Conference, Barcelona 2005; AASLD Practice Guidelines 2007; *Forner et al 2008

Prospective validation* 89 patients with a 5-20 mm noduleSensitivity 33%

CE – US + MRISpecificity 100%

The Diagnosis of HCC at Two Coincidental Imaging Techniques in 55 1-2 cm Liver Nodules in 54 Cirrhotic Patients

CE-US and CT CE-US and MRI CT and MRI

Sensitivity(%) 50 56 56

Specificity (%) 89 90 86

Early arterialhypervascularization

CE-US and CT CE-US and MRI CT and MRI

Sensitivity(%) 26 28 41

Specificity (%) 100 100 100

Portal/venouswash-out

CE-US and CT CE-US and MRI CT and MRI

Sensitivity(%) 21 18 26

Specificity (%) 100 100 100Combined

Sangiovanni et al 2009 submitted

Number and Estimated Cost of the Stepwise Investigations for the Assessment of 55 1-2 cm Nodules in 54 Cirrhotic Patients

1st step 2nd step 3rd step No. FNB Aggreg. Cost (€)

HCC diagnosis by at least 1 single imaging

CE-US CT MRI 33 28,667

MRI CT 33 30,215

CT CE-US MRI 33 28,909

RM CE-US 33 29,346

MRI CT CE-US 33 30,970

CE-US CT 33 30,607

AASLD criteria

CE-US and CT MRI 43 26,440

CE-US and MRI CT 43 30,922

CT and MRI CE-US 43 33,898

Sangiovanni et al 2009 submitted

p=0.031

The Importance of Liver Biopsy To Discriminate Dysplastic Nodes (DN) from Early Hepatocellular Carcinoma (HCC)

Diagnostic Approach Etiology DN HCC Reference

Histology Reticulin HBV/HCV Stromal invasion () Stromal invasion (+) Kojiro et al 2005

Immunostain GPC-3 HBV/HCV

HCV

83-100% negative 72-100% positive Capurro et al 2003

Llovet et al 2006

PCR 13 genes

GPC-3, survivin, LYVE-1

Mixed

HCV

98% discriminative accuracy

94% discriminative accuracy

Paradis et al 2003

Llovet et al 2006

Microarray assays 120 genes

93

genes

HBV

HCV

100% discriminative accuracy Nam et al 2005

Wurmbach et al

2007

The Importance of Liver Biopsy To Identify a Very Early HCC

Nakashima O et al, Hepatology 1995;22:101-105; Kojiro M et al, Sem Liver Dis 2005;25:133-142

Distinctly nodular, early Vaguely nodular, very early

Hypervascular on contrast imaging Hypovascular on contrast imaging

Very early HCC: 17% of all HCCs 1-2 cm in size (Bolondi et al 2005)

5-yr survival after resection: 93% vs 54% early (Takayama et al 1998)

cm cm

A RCT of Population-based Screening for HCC: The Importanceof Early Diagnosis for Improving Liver-Related Mortality

Findings Screened group Control group

(pp x yr = 38,444) (pp x yr = 41,077)

HCC occurrence

Cases 86 67

Early cancer 39 0

Total incidence (per 100,000) 223.7 163.1

Rate ratio (95% CI) 1.37 (0.99, 1.89) reference

Deaths from HCC

Deaths 32 54

Total mortality (per 100,000) 83.2 131.5

Rate ratio (95% CI) 0.63 (0.41, 0.98) reference

RCT in urban Shanghai, abdominal US+AFP every 6 months, HBV / chronic hepatitis

Limitations: patients with cirrhosis unknown, suboptimal compliance (58%), no transplant

Zhang BH, J Cancer Res Clin Oncol 2004;130:417-422

Clinic-based Surveillance for HCC in Cirrhotics: The Importance of Treatment Refinement for Improving Liver-Related Mortality

Sangiovanni A, et al Gastroenterology 2004;126:1005-1014

52

3.7 (1.5-8)

28%

34%

69%

45%

37

3.0 (1.5-6.0)

38%

28%

100%

37%

23

2.2 (1.4-3.1)

43%

5%

92%

10%

HCC, No.

HCC size, cm

Radical treatments

Mortality in treated

Mortality in untreated

Overall mortality

1987-91 1992-96 1997-2001Outcomes

= 0.02

= 0.02

= 0.024

n.s.

= 0.0009

A prospective cohort study of 447 patients with compensated cirrhosis of mixed etiology

in Milan under surveillance with abdominal US and AFP.

p-value

Improved Survival of HCC Patients Is More Influenced by Early Detection Than by Improvement of Medical Care

Chie WC, et al J Evaluat Clin Pract 2007;13:79-85

NH Taiwan University Hospital. Data-base: 1988-1998: A=1989-1993, B=1994-1998

3,445 patients with HCC. 5-yr survival: 29% (A) vs 35% (B), p=0.01.

Cancer type

(B/A) Attributable proportion

of advance in medical care

1 - (B/A) Attributable

proportion of early detection

Breast cancer 0.23 0.77

Cervical cancer 0.50 0.50

Colorectal cancer 0.48 0.52

Gastric cancer 0.24 0.76

Liver cancer 0.34 0.66

Prostate cancer 0.70 0.30

Markov Decision Models to Simulate Cost-utility Ratio of Surveillance

According to AASLD/EASL Guidelines

Study Etiologyof cirrhosis

Incremental cost utilityratio (US$/QALY)

Assumptions

Everson et al 2000 Mixed 35,000 2.5% HCC x year

Arguedas et al 2003 HCV 26,689 50-yr old eligible to OLT

Patel et al 2005 HCV 26,100 46,700 50,400

Hepatic resectionCadaveric liver transplantLiving donor liver transplant

Anderson et al 2008 Mixed 30,700 US alone

Sarasin et al 1996 Mixed 48,293 60 % survival 3-yr after resection

Saab at al 2003 Mixed (Wait list) 74,000

Lin et al 2004 HCV 73,789

Thompson Coon 2007 Mixed £ 31,900 Most alcohol-related

Conclusions

1. According to EASL/AASLD recommendations, patients at high risk for developing HCC should be entered into surveillance programs (Level 1).

2. In most industrialized countries > 50% of the patients with a diagnosis of HCC have been treated with screening and found eligible to radical treatments.

3. The disparity in outcomes between patients diagnosed with an early HCC compared to those with a more advanced tumor, strongly supports screening for HCC.

4. Though surveillance is appropriate when the risk of developing HCC is 1.5% or greater, the cost-effectiveness and the cost-benefit ratios of surveillance vary considerably depending on screening strategies and therapeutic options available.

Clinic-based Surveillance Programmes: The Compliance of Patients with Compensated Cirrhosis

Authors Country Etiology No. Intervals Follow-up Complete drop-outs

(months) (months) (annual rate)

Henrion 2003 Belgium Alcohol 172 6 60 15.3%

Oka 1990 Japan Mixed 140 2-3 36 6.6%

Colombo 1991 Italy Mixed 447 3-12 33 4.7%

Sangiovanni 2004 Italy Mixed 417 6-12 148 4.0%

Henrion 2003 Belgium HCV 64 6 60 3.7%

Velazquez 2003 Spain Mixed 463 3-6 39 2.4%

Pateron 1994 France Mixed 118 6 36 1.1%

Thompson Coon J et al Health Technol Assess 2007;11:No. 34