Prof. Massimo Colombo Co-Chairman Department of Medicine, Head Division of Gastroenterology

1. Paris Hepatitis Conference Paris, 19th-20th January 2009 Screening and diagnosis of hepatocellular carcinoma Prof. Massimo Colombo Co-Chairman Department of Medicine, Head Division of Gastroenterology Fondazione IRCCS Policlinico, Mangiagalli e Regina Elena Università degli Studi di Milano Milano

2. Increasing Incidence of Early Stage HCC in the Referral CentersThe Experience in Japan Ogaki Municipal Hospital, Japan. Data-base: 1968-2004. 1641 patients with a HCC Curative treatments in 1067 (65%) Toyoda H et al, Clin Gastroenterol Hepatol 2006;4:1170-1176

3. 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;42:1208-1236 3JSH Clinical Practice Guidelines for HCC, Makuuchi et al Hepatol Res 2008;38:37-51

4. Are Surveillance Programs Improved by Patients Stratification by Clinical and Histological Scores? 1 Hepatology 1996;23:1112-1118; 2 Hepatology 2003;37:520-527

5. Studies Comparing the Diagnostic Accuracy and Outcome of Surveillance with Different Screening Intervals 1 Blood 2003;102:78-82; 2 J Hepatol 2006;44 Suppl 2:S4; 3 ILCA Proceedings Barcelona 5-7 October 2007, 11

6. Radiological Diagnosis of Hepatocellular Carcinoma in Patients With CirrhosisEASL/AASLD Guidelines Imaging techniques contrast-enhanced US, contrast-enhanced spiral CT and 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 Prospective validation* 89 patients with a 5-20 mm nodule Sensitivity 33% CE – US + MRI Specificity 100% EASL, AASLD & JSH Conference, Barcelona 2005; AASLD Practice Guidelines 2007; *Forner et al 2008

7. The Diagnosis of HCC at Two Coincidental Imaging Techniques in 55 1-2 cm Liver Nodules in 54 Cirrhotic Patients Early arterial hypervascularization Portal/venous wash-out Combined Sangiovanni et al 2009 submitted

8. Number and Estimated Cost of the Stepwise Investigations for the Assessment of 55 1-2 cm  Nodules in 54 Cirrhotic Patients p=0.031 Sangiovanni et al 2009 submitted

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

10. The Importance of Liver Biopsy To Identify a Very Early HCC Distinctly nodular, early Vaguely nodular, very early cm cm 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) Nakashima O et al, Hepatology 1995;22:101-105; Kojiro M et al, Sem Liver Dis 2005;25:133-142

11. A RCT of Population-based Screening for HCC: The Importanceof Early Diagnosis for Improving Liver-Related Mortality RCT in urban Shanghai, abdominal US+AFP every 6 months, HBV / chronic hepatitis Limitations: patients with cirrhosis unknown, suboptimal compliance (58%), no transplant 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 Zhang BH, J Cancer Res Clin Oncol 2004;130:417-422

12. Clinic-based Surveillance for HCC in Cirrhotics: The Importance of Treatment Refinement for Improving Liver-Related Mortality A prospective cohort study of 447 patients with compensated cirrhosis of mixed etiology in Milan under surveillance with abdominal US and AFP. Outcomes 1987-91 1992-96 1997-2001 p-value HCC, No. HCC size, cm Radical treatments Mortality in treated Mortality in untreated Overall mortality 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% = 0.02 = 0.02 = 0.024 n.s. = 0.0009 Sangiovanni A, et al Gastroenterology 2004;126:1005-1014

13. Improved Survival of HCC Patients Is More Influenced by Early Detection Than by Improvement of Medical Care 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. Chie WC, et al J Evaluat Clin Pract 2007;13:79-85

14. Markov Decision Models to Simulate Cost-utility Ratio of Surveillance According to AASLD/EASL Guidelines

15. Conclusions • According to EASL/AASLD recommendations, patients at high risk for developing HCC should be entered into surveillance programs (Level 1). • In most industrialized countries > 50% of the patients with a diagnosis of HCC have been treated with screening and found eligible to radical treatments. • The disparity in outcomes between patients diagnosed with an early HCC compared to those with a more advanced tumor, strongly supports screening for HCC. • 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.

16. Clinic-based Surveillance Programmes: The Compliance of Patients with Compensated Cirrhosis Thompson Coon J et al Health Technol Assess 2007;11:No. 34