1. Intermediate stage HCC treatment options: Y 90 -labelled microspheres

2. Radioembolization with Y 90 -labelled microspheres Y 90 is an integral component of glass 1 or resin beads 2 Half-life of ~64 hours 1,2 Doses supplied 3  20 GBq 1,2 Bead size: approx. 30 micron 1,2 Injected into hepatic arteries that feed liver tumours 1,2 The implanted beads provide: 3 Higher doses of radiation to smaller volumes facilitates a greater tumouricidal effect Minimization of damage to the remaining non-tumour tissue HCC, hepatocellular carcinoma; Y, yttrium. 1. Package insert for TheraSphere®. Available at: http://www.mds.nordion.com/therasphere/physicians-package-insert/package-insert-eu-en.pdf 2. Package insert for SIR-Spheres® micorspheres. Available at: http://www.sirtex.com/files/US20Package20Insert1.pdf 3. Sangro B et al. Dig Dis 2009;27:164  9.http://www.mds.nordion.com/therasphere/physicians-package-insert/package-insert-eu-en.pdfhttp://www.sirtex.com/files/US20Package20Insert1.pdf

3. Current status and use of Y 90 -labelled microspheres Established technique Used in HCC patients with preserved liver function, unresectable tumours and cannot be treated with percutaneous ablation to achieve down-staging of lesions 1,2 Approved in the USA (HDE) and Europe for use in patients with unresectable HCC Not currently included in guidelines for the management of HCC No randomized controlled phase III studies HCC, hepatocellular carcinoma; HDE, humanitarian device exemption (applies to TheraSphere); Y, yttrium. 1. Sangro B et al. Dig Dis 2009;27:164  9; 2. Kulik L et al. J Surg Oncol 2006;94:572  86.

4. Meta-analysis of Y 90 -microsphere radio-embolization in HCC 1 1. Vente et al. Eur Radiol 2009;19:951–9. Tumour response on CTMedian survival (months) StudyPts treated with Y 90 (n) Time to CT post Y 90 (months) CR (%) PR (%) SD (%) PD (%) From diagnosis (or recurrence) From Y 90 Resin microspheres Lau 1994182044 11NR7.1 Lau 1998712027658 9.4 (range 1.8  46.4) NR Lim 2005520255025NR Sangro 2006242NS 12NR 7.1 (95% CI 2.1  12) Jakobs 20075 2323 0NS 0NR Glass microspheres Houle 19897NR002971NR Andrews 199412000100NR Dancey 200022 2323 5165821NR 12 (range 2  42) Carr 20046533284029 Okuda I: 12 (95% CI 2  42) Okuda II: 10 (95% CI 6  20) NR Geschwind 2004100NR Okuda I: 21.0 Okuda II: 1.0 Liu et al 200411 1  1.5 972018NR Salem 200543VaryingNS 21 Okuda I: 24 (95% CI 18  28) Okuda II: 12 (95% CI 9  17) NR Kulik 200635 6 (0.8  16) NS 12NR Sato 200619 5 (1.5  14) NS 21NR

5. Efficacy of Y 90 -labelled microspheres Clinical data in intermediate to advanced HCC show: Possible disease control rates in excess of 80% in selected patients 1,2 In some studies, comparable therapeutic efficacy to TACE for survival in unresectable non-metastatic HCC 3–5 Y 90 radioembolization is significantly more effective with resin microspheres than glass microspheres 2 No prevention of the development of new lesions 6 Survival depends on many factors, including those related to the aggressiveness of disease 6,7 Degree of infiltration Number and bulk of nodules Alpha-fetoprotein levels AST or ALT levels Recent meta-analysis conclusion: 2 “The impact on survival will become known only when the results of phase III studies are published” 1. Sangro B, et al. Dig Dis 2009;27:164–9; 2. Vente et al. Eur Radiol 2009;19:951–9. 3. Carr B, et al. Cancer 2010;116:1305  14; 4. Raoul J, et al. Nat Rev Gastroenterol Hepatol 2010;7:41  9; 5. Lewandowski RJ, et al. Am J Transplant 2009;9:1920–1928; 6. Inarrairaegui M, et al. Int J Radiat Oncol Biol Phys 2010 [E- pub ahead of print]); 7. Goin JE et al. J Vasc Intervent Radiol 2005;16:195–203.