EC915 Eva Gallardo, MD Medical Manager, Biocompatibles UK Drug Eluting Bead: Advanced Applications Colorectal Metastases Neuroendocrine Metastases Combination with RFA

EC915 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 DEB: Clinical Programme

EC915 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

EC915 Advanced Colorectal Cancer The liver is the most common site of metastatic disease % of patients will have synchronous liver metastases at the time of diagnosis. Up to 60% will develop hepatic metastases during the course of their disease Metastatic disease in the liver is the primary determinant of survival in patients with colorectal cancer Low (around 20%) response rates to 5-FU containing chemotherapy regimens

EC915 Median Survival in First Line Phase III Studies Months Best supportive care 5 Biomodulation of 5-FU PiedboisJCO Saltz NEJM 2001(IFL) 14 Irinotecan/5-FU/LV Goldberg JCO 2004 (IFL) Douillard Lancet 2000(Folfiri) De Gramont JCO 2000(Folfox) 16 Oxaliplatin/5-FU/FA GoldbergJCO 2004 ( Folfox) FOLFOXIRI 24.4 Hoschster ASCO TREE2 Oxali/Bev+ salvage CP11 2 drugs+biologic+salvage **subgroup Hurwitz NEJM 2004IFL/Bev+ salvage Oxali 25.1 BMJ 1993 FOLFOX/FOLFIRI 22 Tournigand JCO 2004 sequential 2 drugs Falcone ASCO 2006concurrent 3 drugs - no biologics

EC915 Rationale for Chemoembolization treatment in metastatic CRC Blood supply from hepatic artery Maximize tumour cell kill while minimizing toxicity to normal tissues (heavily systemically treated patients) Increase tumour response throughout increased drug delivery into tumour Increase resectability rates

EC915 Disease control after Chemoembolization n= 207 Local tumour control: –Partial response: 12%, stable: 51%, progression: 37% Survival rates: –1y: 62%, 2y: 38% Median survival times: –From diagnosis: 3.4y, from TACE: 1.34y Prof T Vogl, ASCO 2007

EC 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) Measurable lesions with size > 1cm Tumour burden <70% of liver volume Presence of minimal extrahepatic sites Performance Status: 0-2 (WHO criteria), life expectancy >3 months, age < 86 years Normal or 2xN bilirubine Irinotecan Bead in Advanced Colorectal Cancer: Patient Selection

EC915 Diagnostic angiography (DSA) was performed Under fluoroscopic guidance, a solution of DC beads loaded with Irinotecan and mixed with non-ionic contrast was injected into: RHA 39%, LHA 36%, RHA & LHA 25% Maximum dose 4 ml (2ml of mm and 2ml of mm) with 200mg of Irinotecan 2-3 TACE 4 weeks Irinotecan Bead in Advanced Colorectal Cancer: Methods

EC TACE procedures 48 with 100mgr Irinotecan into 2ml DC Bead 98 with 200mgr Irinotecan into 4ml DC Bead (no significant toxicity observed) 100% technical success One case of acute pancreatitis, resolved spontaneously Irinotecan Bead in Advanced Colorectal Cancer: Feasibility

EC915 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

EC915 Prophylactic treatment against nausea Tropisetron 5mg, 1 vial before TACE and at +6 hours,Prednisone 25mg tb am and pm day 0,+1,+2,+3,+4,+5 Prophylactic treatment against pain Morphine 10mg, 1 vial, 30 minutes before TACE and at +6 hours. Intra-arterial Lidocaine 5ml just before TACE. Prophylactic treatment against infection Cefazolin 2000mg am and pm day 0,+1,+2 On day +1, +2 at am and pm following observed symptoms. Postembolization-syndrome: Selected Therapy Irinotecan Bead in Advanced Colorectal Cancer: Toxicity

EC915 The median follow-up was 15.4 months 1 month CT scan showed reduction of metastatic CE 85%, range % 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

EC915 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

EC months after TACE Irinotecan Bead in Advanced Colorectal Cancer: Cases

EC months after TACE Irinotecan Bead in Advanced Colorectal Cancer: Cases

EC915 TACE with Irinotecan DC Bead could be proposed as palliative therapy for unresectable pretreated Liver Metastases from CRC Promising preliminary results should be confirmed in further studies in larger population Irinotecan Bead in Advanced Colorectal Cancer: Conclusion

EC915 Principal Investigator: Thierry De Baere, MD Chief of Interventional Radiology Department Institut de Cancérologie Gustave Roussy - Villejuif - France Neuroendocrine Metastasis

EC915 Neuroendocrine Tumours Variety of primaries with shared characteristics including hormone secretion, high vascularization and somatostatin receptor expression Tumours arise most often from the gastro-intestinal tract and mainly the small bowel The malignancy grade and the stage at diagnosis are the two major prognostic factors

EC915 Management Protocol

EC915 Reported HAE and HACE Series Carcinoid tumoursIslet cell carcinomas HACEHAEHACEHAE Study % CR + PR (no.)Study % CR + PR (no.)Study% CR + PR (no.)Study % CR + PR (no.) Hazarizadeh et al., (4/8)Hanssen et al., (5/7)Carrasco et al., (3/3)Carrasco et al., (3/6) Rusznieweski et al., 1993]33.3 (6/18)Moertel et al., (16/23)Mavligit et al., (4/5)Moertel et al., (14/17) Therasse et al., (6/17)Wangberg et al., (17/40)Kim et al., (7/14)Eriksson et al., (2/12) Kim et al., (4/16)Eriksson et al., (11/29)Dominguez et al., (4/7)Ajani et al., (12/20) Dominguez et al., ,0 (4/8)Carrasco et al., (5/6)Rusznieweski et al., (0/5) Roche et al., (6/14)Loewe et al., (16/22) Drougas et al., (1/15) Average32.0 (31/96)Average55.0 (70/127) Average53.0 (18/34)Average56.0 (31/55)

EC915 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 mm loaded with up to 100mg doxorubicin Concomitant treatment with long-acting ST analog

EC915 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

EC915 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

EC915 Doxorubicin Bead in NET: Cases

EC915 Doxorubicin Bead in NET: Cases

EC915 Tumour resected 2 months after PRECISION TACE Doxorubicin Bead in NET: Cases

EC915 TACE with doxorubicin bead yielded a 90% response rate in patients with progressive liver metastases from a GEP tumor without severe complications These promising preliminary results warrant a comparative study in a larger population Doxorubicin Bead in NET: Conclusion

EC915 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

EC915 HCC PST 0-2, Child-Pugh A-B PST > 2 Child Pugh C Very early stage Single < 2 cm Early stage Single or 3 < 3 cm PS 0 Advanced stage Portal invasion N1 – M1 PS 1-2 Terminal stage Intermediate stage Multinodular PS 0 BSC PST 0 Child Pugh A New agents ResectionTransplantAblation TACE Single No portal HT Normal bilirubin Associated diseases No Yes

EC915 Bio-Heat Equation Coagulation Necrosis Energy Deposited Tissue Interactions Heat Loss =x- RFA: Inherent Limitations modified from Goldberg SN et al, AJR 2000

EC915 Vessel Sub-lethal heating (45-50 °C) 50 °C RFA: Inherent Limitations

EC915 modified from Ahmed et al, Radiology 2005 RFA plus Doxorubicin vs RFA Alone in Animal Tumour Models

EC915 RF-induced coagulation Increased peripheral necrosis Normal tissue modified from Ahmed et al, Radiology 2005 RFA plus Doxorubicin vs RFA Alone in Animal Tumour Models

EC915 Rossi S, Radiology 2000 Yamasaki T, Cancer 2001 Yamakado K et al,JVIR 2002 Gasparini D, Radiol Med 2002 Akamatsu M, Liver Int 2004 Luo BM, World J Gastroenterol 2005 Maluccio M, JVIR 2005 Shen SQ, Hepatogastroenterology 2005 Yamasaki T, J Gastroenterol 2005 Liu YM, World J Gastroenterol 2006 Veltri A, Eur Radiol 2006 Kurokohchi K, Oncol Rep 2006 Lim HS, AJR 2006 Takaki H, JVIR 2007 Kobayahi M, Liver Int 2007 Helmberger T, Digestion 2007 Wang JB, Qual Life Res 2007 Liao GS, Eur J Surg Oncol 2008 Fuke H, Aliment Pharmacol Ther 2008 Yamakado K, Radiology 2008 Combined TACE / TAE and RFA in HCC 20 clinical studies all “support” the combined approach

EC915 Lencioni R et al, J Hepatol 2008 (in press) DC Bead (Biocompatibles, UK): embolic microsphere that has the ability to actively sequester doxorubicin hydrochloride from solution and release it in a controlled and sustained fashion Hypothesis: intra-arterial administration of doxorubicin eluting bead to HCC tumours incompletely killed by RFA induces necrotic phenomena in peripheral areas exposed to sub-lethal heating, improving tumour response DEB-Enhanced RFA of HCC: A Pilot Study Background / Hypothesis

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Design / Enrollment Criteria Prospective, intention-to-treat, single-arm pilot study Primary endpoints: safety and tumour response Inclusion criteria - Adult patient with single HCC 3.0 – 7.0 cm - Residual viable tumour at CT / MRI 1-2 hrs after RFA - Child-Pugh class A, ECOG 0, ASA ≤ 3 - PT ratio > 50%, platelets > 50,000/mm3 Exclusion criteria - Eligibility for liver resection or transplantation - Vascular invasion / extrahepatic disease - Any previous treatment for HCC

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Materials and Methods 20 pts (mean age, 70 ± 6 ) enrolled 09/05 – 11/06 - Tumour diameter cm (mean, 5.0 cm ± 1.4) 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 μm beads - Additional loads ( / 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

EC915 61% + Ablation Volume (mm 3 ) 0,000 20,000 40,000 60,000 80, , , , , ,000 Standard RFADEB-Enhanced RFA DEB-Enhanced RFA of HCC: A Pilot Study Results – Change in Ablation Volume

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Results – Clinical Case # 2 Pre-treatment CT 6 cm

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Results – Clinical Case # 2 MRI after standard RFA

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Results – Clinical Case # 2 DEB administration

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Results – Clinical Case # 2 MRI after DEB administration

EC CRIRPD 14 6 DEB-Enhanced RFA of HCC: A Pilot Study Results – Target Tumour Response CRIRPD Final Response (mean follow-up, 1 year) Initial Response (1-month CT / MRI))

EC915 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

EC DEB-enhanced RFA (n = 20) months % DEB-Enhanced RFA of HCC: A Pilot Study Results – Overall Survival 92%

EC915 DEB-Enhanced RFA of HCC: A Pilot Study Results – Conclusion This pilot clinical study provides the first evidence of the synergy between RF ablation and local delivery of a chemotherapeutic agent in human cancer treatment Intraarterial DEB administration substantially increased the effect of RF ablation and did not cause any major complication. DEB-enhanced RF ablation induced a high rate of CR and has potential to become the standard of care for uninodular nonsurgical HCC resistant to standard RF treatment