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JF Geschwind, MDProfessor 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

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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!

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PEI/RFA Sorafenib

Stage 0PS 0, Child–Pugh A

Very early stage (0)

1 HCC <2cmCarcinoma 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 TACEResection Symptomatictreatment Curative treatments Randomised 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 DPS >2, Child–Pugh C

HCC

Intermediate stage (B)Multinodular,

PST 0

Stage A–CPS 0–2, Child–Pugh A–B

BCLC staging system and treatment strategy

HCC = hepatocellular carcinoma; BCLC = Barcelona Clinic Liver CancerPEI = percutaneous ethanol injection; RFA = radiofrequency ablationTACE = transarterial chemoembolisation; PST = performance status

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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)

Do

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Time Post-Procedure

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LTime Post-Procedure

baseline

5 min20 min

40 min

60 min

2 h 6 h 24 h48 h

7 d

1000

800

600

400

200

0

baseline

5 min20 min

40 min

60 min

2 h 6 h 24 h48 h

7 d

1000

800

600

400

200

0

DEB-TACE

Conventional TACE

DEBDOX: DC Bead®, Drug-Eluting Bead doxorubicinVarela M et al. J Hepatology. 2006; 46(3):474-481.

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Single Center Phase II Trial of DEBDOX in Patients with Unresectable HCC

Variable Value

Number patients enrolled 20

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/other 5/8/7

Mean tumor size in cm (range) 6.9 (1.9-16.2)

Number Tumors (1,1+, Multifocal)

10/6/4

Portal vein thrombosis (Y/N) 4/16

AFP (ng/ml) 1215Reyes D et al. Cancer J. 2009

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Kaplan-Meier Survival Curves

Time Months403020100

100

80

60

40

20

0

Sur

viva

l Pro

babi

lity

%

OSPFS

Reyes D et al. Cancer J. 2009

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PRECISION V: Overall 6-month Tumor Response Rates

p = 0.11

Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response

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6-month Response in More Advanced Patients

DC Bead® demonstrated statistically significant advantage in advanced patientsObjective Response (p=0.038) and Disease Control (p=0.026)

P < 0.05

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p=0.012*

Inci

den

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f d

oxo

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icin

-rel

ated

AE

s (%

)

35

30

25

20

15

10

5

0 DC Bead® cTACE

Alopecia

Marrow suppression

Mucositis

Skin discoloration

DC Bead® cTACE

PRECISION V trial1: DC Bead® was associated with a significantly lower incidence of doxorubicin-related AEs than cTACE

AE = adverse event1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;44:41–52

2. http://www.biocompatibles.com/media/press-releases/2009/06-08-2009.aspx

*p=0.0001 for analysis with assumption of independence of events

DC Bead® is approved in 40 countries worldwide, including the

USA (as LC Bead™) and Europe2

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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 = 0.008

Malagari et al, Cardiovasc Intervent Radiol. 2009 Nov 24

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Clinical EvidenceInvestigator Level of

evidenceNumber patients

CP score CR and PR Survival *

Varela (2007) 3iiDiii 27 A 75% (EASL) 2YR 89%

Geschwind (2009) 3iiiDiii 20 A(15)/B(5) 89% (RECIST)

95% (EASL)

26 months

Poon (2007) 3iiDiii 35 A 50% (RECIST)

70% (EASL)

N/A

Grosso (2008) 3iiiDiii 50 A(46)/B (4) 74.8 % (EASL) N/A

Malagari (2008) 3iiDiii 71 A (27)/B (44) 80.6 % (EASL) 2YR 91%

Forner (2008) 27 A 50% (RECIST) N/A

Lammer (2008) 3iiDiii 30 A (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= 0.038. Fewer dox side effects: p=0.0001

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Conclusions

DEBDOX: Proven Rationale Extension of cTACE Excellent PK profile Minimal toxicities

Efficacy: Tumor response 75-85% EASL Survival: ~26 months BCLC B-C

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2. How? Technical Considerations: Towards a Standardized Protocol

Drug delivery not embolotherapy!Drug delivery not embolotherapy!

1. Choice of particle size2. Choice of drug: doxorubicin vs. irinotecan3. Catheter placement4. Actual delivery (how? Contrast or not?)5. End point (?)

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1.

Optimizing Drug Delivery: Importance of Particle Size

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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 KH, Liapi E, Vossen JA, Buijs M, Ventura VP, Georgiades C, Hong K, Kamel I, Torbenson MS, Geschwind JF. J Vasc Interv Radiol. 2008 Oct;19(10):1490-6.

IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 300-500µm

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IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 100-300µm

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Drug-Eluting Beads for liver embolization: Concentration of doxorubicin in tissue and in beads in a pig model

100-300μm or 700-900μm 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 100-300μm induced more necrosis than 700-900μm

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. 2010 Feb;21(2):259-67Dreher M et al. GEST 2010

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1.

Optimizing Drug Delivery: Importance of Particle Size

SMALL

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Complete necrosis on MR imaging

DC Bead® [DEBDOX] in Patients with HCC

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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

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Histopathology: Extensive necrosis + no viable tumor cells

DEB within necrotic tumor

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2.

Optimizing Drug Delivery: What drug?

Doxorubicin: HCC, NET

Irinotecan: CRC (?), No data

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3.

Catheter Placement

Selective?

YES

1.Better control

2.Minimize reflux

3.Better visualization of beads

2465 yo woman Child B with large HCC: First Treatment

25Post-treatment #1: Residual viable tumor

Pre-treatment

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Second Treatment

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

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4.Actual Delivery

1. Must use microcatheter2. Use cone beam CT for targeting3. Visibility of beads critical4. Mix with contrast (4:1)5. Inject slowly (1 ml/min)

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Usefulness of Cone Beam CT

Imaging: Research and Clinical Use

1. Visualize the tumor2. Target the tumor (drug delivery)3. Proof of success = predicting response:

Tumor perfusionTumor segmentation

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DEBDOX in Patient with HCC: Usefulness of Cone Beam CT

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5.

End Points

1. Entire planned dose administered

2. Stop before stasis!!

3. No need for further bland embolization

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ConclusionsDrug-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

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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