1. EC916 Eva Gallardo, MD Medical Manager, Biocompatibles UK Drug Eluting Bead: Clinical Updates and Histological Data

2. EC916 Doxorubicin BeadIrinotecan Bead Primary Liver Cancer Colorectal Metastases Very Early/Early Stage Prior to resection Bridge to transplant RFA + PRECISION TACE Intermediate Stage Precision I Precision II Precision V Advanced Stage Sorafenib + PRECISION TACE Secondary Liver Cancer Other Primary Cancers Renal Breast MelanomaGastric Neuroendocrine Cholangiocarcinoma Sarcoma Early CT Lines Late Stage DC Bead: Clinical Programme

3. EC916 Investigators: Camillo Aliberti, MD Giammaria Fiorentini, MD Department of Diagnostic and Interventional Radiology, Delta Hospital AUSL Ferrara, Ferrara Italy Department of Oncology, General Hospital San Giuseppe, Empoli, Florence, Italy PRECISION TACE in treatment of Colorectal Metastases

4. EC916 62 patients (M/F = 42/20), median aged 64.6 (range 42-85) Not operable and pretreated at least two lines of chemo (range 2-6) Maximum dose 4 ml (2ml of 100-300mm and 2ml of 300- 500mm) with 200mg of Irinotecan 2-3 TACE 4 weeks Irinotecan Bead in Advanced Colorectal Cancer: Patient Selection

5. EC916 Postembolization-syndrome RUQP (G2-G3) 100% Fever (G2) 90% Nausea and Vomiting (G2- G3) 100% Increased Transaminases (G2-G3) 80% Irinotecan Bead in Advanced Colorectal Cancer: Toxicity

6. EC916 The median follow-up was 15.4 months 1 month CT scan showed reduction of metastatic CE 85%, range 75-100% in all patients RECIST at 3 months: 78% 55/62 pts (90%) declared a general improvement of QoL lasting 6.5 months, range 3-12 Irinotecan Bead in Advanced Colorectal Cancer: Response to Treatment

7. EC916 Median survival not reached at 22 months Median Free Time from symptoms 5.3 (5-20 months) Median Time to further chemoteraphy 6.3 (5-22 months ) Irinotecan Bead in Advanced Colorectal Cancer: Survival

8. EC916 18 months after TACE Irinotecan Bead in Advanced Colorectal Cancer: Cases

9. EC916 02.2005 09.2005 6 months after TACE Irinotecan Bead in Advanced Colorectal Cancer: Cases

10. EC916 Principal Investigator: Thierry De Baere, MD Chief of Interventional Radiology Department Institut de Cancérologie Gustave Roussy - Villejuif - France Neuroendocrine Metastasis

11. EC916 Doxorubicin Bead in NET: Materials and Methods 20 patients with liver metastases from low-grade GEP tumour Progressive liver disease on two subsequent imaging studies according to RECIST criteria Disease predominant to the liver Up to 4ml DC Bead 500-700mm loaded with up to 100mg doxorubicin Concomitant treatment with long-acting ST analog

12. EC916 Doxorubicin Bead in NET: Results 34 sessions (6 unilobar, 14 bilobar) RECIST 3M: –16/20 (80%) partial response –3/20 (10%) stable disease –1/20 (15%) progressive disease After a median follow-up of 15 months (6-24), disease remained controlled without tumour progression in 45% 1 patient become resectable Median Time to Progression: 15 months

13. EC916 Post-embolisation syndrome: –< 7 days in 67% sessions –> 7 days in 22% sessions –No symptoms in 11% sessions Hypodense subsegmental peripheral areas (TACE- induced necrotic liver tissue?) in 5 patients at 1 month CTscan 1 death: resected patient due to postoperative septic complications Doxorubicin Bead in NET: Toxicity

14. EC916 Doxorubicin Bead in NET: Cases

15. EC916 Doxorubicin Bead in NET: Cases

16. EC916 Principal Investigator: Riccardo Lencioni, MD Associate Professor of Diagnostic and Interventional Radiology Department of Oncology, Transplants, and Advanced Technologies in Medicine – Pisa University, Italy Combined PRECISION TACE/RFA: Results and Outcome

17. EC916 Vessel Sub-lethal heating (45-50 °C) 50 °C RFA: Inherent Limitations

18. EC916 DEB-Enhanced RFA of HCC: A Pilot Study Design / Enrollment Criteria 20 pts (mean age, 70 ± 6 ) with residual viable tumour at CT / MRI 1-2 hrs after RFA - Tumour diameter 3.3-7.0 cm (mean, 5.0 cm ± 1.4) - Child-Pugh class A, ECOG 0 - PT ratio > 50%, platelets > 50,000/mm3 Excl: - Eligibility for liver resection or transplantation - Vascular invasion / extrahepatic disease - Any previous treatment for HCC

19. EC916 DEB-Enhanced RFA of HCC: A Pilot Study Materials and Methods Follow-up period 6-20 months (mean, 12 months ± 5) DC Bead (Biocompatibles) injection < 24 hrs of RFA - 50 mg doxorubicin in 2 ml of 100-300 μm beads - Additional loads (100-300 / 300-500 µm) if needed Tumour response: RECIST criteria - EASL amendment - CR: absence of enhancement at 1-month CT / MRI - Confirmed CR: CR lasting no less than 6 months - OR: confirmed CR target lesion, no new lesions

20. EC916 61% + Ablation Volume (mm 3 ) 0,000 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 Standard RFADEB-Enhanced RFA DEB-Enhanced RFA of HCC: A Pilot Study Results – Change in Ablation Volume

21. EC916 DEB-Enhanced RFA of HCC: A Pilot Study Results – Clinical Case # 2 Pre-treatment CT 6 cm Post-RFA Post-TACE

22. EC916 Target lesions Table. Overall Response at the End of Follow-Up New lesions CR PR CR / PR PD Note: Numbers are numbers of patients. Overall number of patients: 20. No No Yes Yes / No Overall response CR PR PD No. (%) 10 (50%) 5 (25%) 3 (15%) 2 (10%) DEB-Enhanced RFA of HCC: A Pilot Study Results – Overall Response

23. EC916 061218 24 0 20 40 60 80 100 DEB-enhanced RFA (n = 20) months 30 100% DEB-Enhanced RFA of HCC: A Pilot Study Results – Overall Survival 92%

24. EC916 Doxorubicin Bead prior to liver transplant

25. EC916 TACE Prior to Transplant Major issue = Dropout rate (30-40%)Major issue = Dropout rate (30-40%) Role of TACE:Role of TACE: Patients within Milan criteria (maintain in waiting list)Patients within Milan criteria (maintain in waiting list) Patients outside Milan criteria (for downstaging to fullfil Milan criteria)Patients outside Milan criteria (for downstaging to fullfil Milan criteria) Induce high hystological tumour response rateInduce high hystological tumour response rate Decrease recurrence rates?Decrease recurrence rates?

26. EC916 Dr Citron –Atlanta, US Retrospective study 9 listed patients (>Child A-B, single nodules, mean tumour size 2cm (0.3-5.1) 1-3 treatments prior to transplant 100-300 and/or 300-500mm DC Bead with up 150mg doxorubicin Liver transplant (1-281 days post-treatment)

27. EC916 Results CTscan: –Complete necrosis 88% patients Histology: –Complete necrosis 77% patients –2 non-complete necrosis: Patient transplanted 8 hours after TACE with no necrosis Patient with residual 0.5cm viable tumour within 7.5cm necrotic tumour

28. EC916 Dr Nicolini - Italy Retrospective study Doxorubicin Bead vs TAE 16 patients (15 waiting list/ 1 outside Milan) DC BeadTAE HCV HDV + HBV Others 332332 404404 Child-Pugh A Child-Pugh B 5353 6262 Mean tumour size (cm)3.03.4 Single 2 nodules 7171 5353 1-4 treatments until complete RX response DC Bead arm: 100-300mm DC Bead with 50mg epirubicin TAE:100-300mm Embosphere

29. EC916 Tumour Response DC BeadTAE CTscan Response* Complete Necrosis Partial Necrosis (>70%) 88 12 45 55 Histological Response* Complete Necrosis Necrosis >70% Necrosis <50% 78 22 0 P=0.04 27 54 19 * % Tumour response by tumours 62.5% DC Bead achieved complete RX response after one treatment vs 12.5% in TAE 15 patients alive with no recurrence

30. EC916 Prof Goffette - Belgium 16 patients: –9 within the Milan criteria for LT –7 outside the Milan criteria for LT Diameter > 5 cm 4 More than 3 tumours 3 Mean tumour size 5.4 cm (2.3-7.8), 2 portal vein thrombosis Standardized DC Beads doses and sizes: –4ml (2 vials) of 300-500 µm particles loaded with 25mg/ml doxorubicin:100 mg Doxo/session Additional unloaded particles (300-500,500-700µ) if persitent flow Sequential treatment every 3 months (Max 4) Alternate treatment if bi-lobar lesions

31. EC916 Procedural Results Mean number of sessions2.7 4pts:1, 6pts:2, 7pts:3, 1pt:4 Serious adverse event Cholecystitis1 30-day mortality0 Post-embol syndrome15 Transient impaired liver function12

32. EC916 Transplanted patients10 Delay: 6.5 months (2-15) Biliary complications: 3 Follow-up: 7.5 months – 1 recurrence at 5 m (40% necrosis) Patients on waiting list4 Deaths2 Pneumonia Terminal liver failure Significant downstaging in 6/7 patients Clinical Results

33. EC916 Complete4(25%) Partial11(69%) – Residual peripheral enhancement9 – Persistent enhanced nodules4 Stable Disease1 Progressive Disease0 Objective Response15(94%) Results Imaging (EASL)

34. EC916 Histological Response PATHOLOGIC ASSESSMENT All patients (n=12) Vascular permeation Portal thrombosis Recurrence After OLT (n=10) RESPONSE Complete tumor necrosis 5 (42%)00/5 (0%) Partial tumor necrosis ≥75% and <99% 6 (50%)20/4 (0%) NO RESPONSE Incomplete tumor necrosis < 50% 1 (8%)11/1 (100%)

35. EC916 Surgical Complications Complicated arterial anastomosis7 – Co/proper Hep. Art. occlusion4 – Pedicular inflammation3 – Early arterial occlusion…redo-OLT in 1 Difficult biliary anastomosis3 Severe chronic cholecystitis4

36. EC916 46 yr old male: Bilobar HCC ( >7cm seg IV) Downstaging before LT First TACE session left lobe

37. EC916 Repeated controls CT after first session Second TACE (right lobe) and control CT……waiting list 46 yr old male: Bilobar HCC ( >7cm seg IV) Downstaging before LT