1 JF Geschwind, MD Professor Radiology, Surgery, and Oncology Director, Vascular and Interventional Radiology Johns Hopkins University School of Medicine Baltimore, Maryland Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011: The Case for a Treatment Standard

2 1. Why Drug-elutingTechnology? Clear Rationale: 1.Maximize drug delivery 2.Consistent (scientifically reproducible) 3.Long lasting effect/slow release (sustained) 4.Tumor effect vs. systemic side effects WE HAVE COME A LONG WAY!

3 PEI/RFA Sorafenib Stage 0 PS 0, Child–Pugh A Very early stage (0) 1 HCC <2cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules <3cm, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1–2 End stage (D) Liver transplantation TACE Resection Symptomatic treatment Curative treatmentsRandomised controlled trials Associated diseases YesNo 3 nodules ≤3cm Increased Normal 1 HCC Portal pressure/ bilirubin Llovet JM, et al. J Natl Cancer Inst 2008;100:698–711 Stage D PS >2, Child–Pugh C HCC Intermediate stage (B) Multinodular, PST 0 Stage A–C PS 0–2, Child–Pugh A–B BCLC staging system and treatment strategy HCC = hepatocellular carcinoma; BCLC = Barcelona Clinic Liver Cancer PEI = percutaneous ethanol injection; RFA = radiofrequency ablation TACE = transarterial chemoembolisation; PST = performance status

4 Chemoembolization of Hepatocellular Carcinoma With Drug-Eluting Beads: Efficacy and Doxorubicin Pharmacokinetics  27 patients with Child-Pugh A  Response rate assessed by CT at 6 months  Response rate: 75%  1- and 2-year survival: 92% and 89% (median follow- up of 28 months) Doxorubicin at serum, ng/mL Time Post-Procedure Doxorubicin at serum, ng/mL Time Post-Procedure baseline 5 min20 min40 min60 min2 h6 h24 h48 h7 d baseline 5 min20 min40 min60 min2 h6 h24 h48 h7 d DEB-TACE Conventional TACE DEBDOX: DC Bead®, Drug-Eluting Bead doxorubicin Varela M et al. J Hepatology. 2006; 46(3):

5 Single Center Phase II Trial of DEBDOX in Patients with Unresectable HCC VariableValue Number patients enrolled20 Mean age, years (range)64 (41-85) Sex (M/F)12/8 Child-Pugh (A/B/C)15/5/0 BCLC (B/C)8/12 ECOG (0/1/2)9/10/1 Hepatitis B/C/other5/8/7 Mean tumor size in cm (range)6.9 ( ) Number Tumors (1,1+, Multifocal) 10/6/4 Portal vein thrombosis (Y/N)4/16 AFP (ng/ml)1215 Reyes D et al. Cancer J. 2009

6 Kaplan-Meier Survival Curves Time Months Survival Probability % OS PFS Reyes D et al. Cancer J. 2009

7 PRECISION V: Overall 6-month Tumor Response Rates p = 0.11 Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response

8 6-month Response in More Advanced Patients DC Bead ® demonstrated statistically significant advantage in advanced patients Objective Response (p=0.038) and Disease Control (p=0.026) P < 0.05

9 p=0.012* Incidence of doxorubicin-related AEs (%) DC Bead ® cTACE Alopecia Marrow suppression Mucositis Skin discoloration DC Bead ® cTACE PRECISION V trial 1 : DC Bead ® was associated with a significantly lower incidence of doxorubicin-related AEs than cTACE AE = adverse event 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;44:41– *p= for analysis with assumption of independence of events DC Bead ® is approved in 40 countries worldwide, including the USA (as LC Bead™) and Europe 2

10 Prospective Randomized Comparison of Chemoembolization with Doxorubicin-Eluting Beads and Bland Embolization with Bead Block for Hepatocellular Carcinoma Evaluate the added role of a chemotherapeutic in TACE of intermediate-stage HCC Group A (n = 41) DEBDOX Group B (n = 43) bland embolization EASL criteria and AFP At 6 month: DEBDOX CR 27% PR 46% Bland embo CR 14% PR 42% Tumor Recurrence: Bland embolization >> DEBDOX (78% vs. 46% at 12 months) TTP: DEBDOX >>Bland embolization 42 +/- 9.5 vs. 36 +/- 9.0 weeks, p = Malagari et al, Cardiovasc Intervent Radiol Nov 24

11 Clinical Evidence InvestigatorLevel of evidence Number patients CP scoreCR and PRSurvival * Varela (2007)3iiDiii27A75% (EASL)2YR 89% Geschwind (2009)3iiiDiii20A(15)/B(5)89% (RECIST) 95% (EASL) 26 months Poon (2007)3iiDiii35A50% (RECIST) 70% (EASL) N/A Grosso (2008)3iiiDiii50A(46)/B (4)74.8 % (EASL)N/A Malagari (2008)3iiDiii71A (27)/B (44)80.6 % (EASL)2YR 91% Forner (2008)27A50% (RECIST)N/A Lammer (2008)3iiDiii30A (26)/B (4)40% (RECIST) 44% (EASL) N/A Lencioni- PRECISION V (2010) 1iiDiii 212 (102 DEB) A (77)/B (16)52% (RECIST) 63% (EASL) N/A *Survival data on DEBDOX are restricted to less than 4 years and longer term follow-up results will be published soon. **DEB vs TACE: p=0.11. DEB advantage for CP B/ECOG 1/bilobar or recurrence: p= Fewer dox side effects: p=0.0001

12 Conclusions  DEBDOX: Proven Rationale  Extension of cTACE  Excellent PK profile  Minimal toxicities  Efficacy: Tumor response 75-85% EASL  Survival: ~26 months BCLC B-C

13 2. How? Technical Considerations: Towards a Standardized Protocol Drug delivery not embolotherapy! 1. Choice of particle size 2. Choice of drug: doxorubicin vs. irinotecan 3. Catheter placement 4. Actual delivery (how? Contrast or not?) 5. End point (?)

14 1. Optimizing Drug Delivery: Importance of Particle Size

15 Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy. Lee KHLee KH, Liapi E, Vossen JA, Buijs M, Ventura VP, Georgiades C, Hong K, Kamel I, Torbenson MS, Geschwind JF. J Vasc Interv Radiol Oct;19(10): Liapi EVossen JABuijs M Ventura VPGeorgiades CHong KKamel I Torbenson MSGeschwind JF IA Therapy for Vx-2 Liver Tumor: Iron-oxide Labeled Microspheres µm

16 IA Therapy for Vx-2 Liver Tumor: Iron-oxide Labeled Microspheres µm

17 Drug-Eluting Beads for liver embolization: Concentration of doxorubicin in tissue and in beads in a pig model  μm or μm loaded with 37.5 mg dox/mL  Livers analyzed 28 or 90 days after embolization  DEBs eluted 43% of their initial drug load after 28 days and 89% after 90 days  Drug detected at distances as far as 600μm from bead edge  μm induced more necrosis than μm beads (p=.0036)  MicroCT analysis: Small beads distal arteries + homogeneous distribution  Doxorubicin concentration declines with increasing distances from the bead edge (still enough to be cytotoxic in vitro) Namur J et al. J Vasc Interv Radiol Feb;21(2): Dreher M et al. GEST 2010

18 1. Optimizing Drug Delivery: Importance of Particle Size SMALL

19 Complete necrosis on MR imaging DC Bead ® [DEBDOX] in Patients with HCC

20 Histological findings and tumor response 48 y/o female, right lobe lesion, s/p 3 treatments with DEBDOX Gross specimen after resection showing complete necrosis

21 Histopathology: Extensive necrosis + no viable tumor cells DEB within necrotic tumor

22 2. Optimizing Drug Delivery: What drug? Doxorubicin: HCC, NET Irinotecan: CRC (?), No data

23 3. Catheter Placement Selective? YES 1.Better control 2.Minimize reflux 3.Better visualization of beads

24 65 yo woman Child B with large HCC: First Treatment

25 Post-treatment #1: Residual viable tumor Pre-treatment

26 Second Treatment

27 MRI Post-treatment #2 No recurrence 29 months post initial treatment

28 4. Actual Delivery 1. Must use microcatheter 2. Use cone beam CT for targeting 3. Visibility of beads critical 4. Mix with contrast (4:1) 5. Inject slowly (1 ml/min)

29 Usefulness of Cone Beam CT Imaging: Research and Clinical Use 1.Visualize the tumor 2.Target the tumor (drug delivery) 3.Proof of success = predicting response: Tumor perfusion Tumor segmentation

30 DEBDOX in Patient with HCC: Usefulness of Cone Beam CT

31 5. End Points 1. Entire planned dose administered 2. Stop before stasis!! 3. No need for further bland embolization

32 Conclusions Drug-Eluting Beads in 2011: Why, how and when?  WHY? Rationale ESTABLISHED  HOW? Technical considerations NEARING CONSENSUS (panel of experts)  Bead size: Nearly there! SMALL >>large  Drug: Doxorubicin (YES) vs. irinotecan (NO)  Catheter position: SELECTIVE  End point: FULL DOSE (no stasis)  Unknown: Frequency treatment/dosing  WHEN? HCC: Good data NET: On-going studies, CRC: On-going studies

33 DISCLOSURES  Grant support: Genentech, Bayer Healthcare, Nordion, Biocompatibles, Abdulmalik Research Fund, Alice Pratt Liver Cancer Fund, NIH/NCI, DOD, RSNA, SIR  Consultant: Philips Medical System, Bayer Healthcare, Nordion, Biocompatibles, Guerbet, PreScience  Patent: Use of 3-BrPA as an anti-cancer agent  Founder: PreScience Pharma