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Drug Eluting Beads for TACE

T de Baere Institut Gustave Roussy, Villejuif

• Clinical results of Drug eluting beads - Rational - HCC - NET

(neuroendocrine tumors)

or GEP

(gastroanteropancreatic endocrine tumors) -

Colrectal cancer metastases

Rational

100000 80000 60000 40000 20000 0

Carboplatin IV IAH Liver IAH+embolization Tumor

(Pohlen, U et al. J Surg Res 2000; 92 : 165-70)

R art Q CL A (1 - E r )

• • •

High clearance (CL) High extraction ratio (Er)

Er at first pass Keep it longer in the liver

Low blood flow (Qa)

Embolization 101 81

R art

61 41 21 1 24 18

Q A (L/h)

12 6 0.9

0.5

E r

0.1

0.45

Rational

Doxorubicin Pharmacokinetics

Pharmakokinetic in animal

450 400

Doxorubicin in tumor

0.40

0.35

Doxorubicin in plasma

350 300 250

IA free doxorubicin IA DEB doxorubicin IA free doxorubicin IA DEB doxorubicin

0.30

0.25

0.20

IA Control DEB 200 150 100 IA Control DEB 0.15

50 0 0.10

200 300 400 0.05

0 100

Courtesy of J Geschwind

0.00

0 1

Courtesy of J Geschwind

2

Time (hrs)

3 4

Time (hrs)

Rational

Doxorubicin Pharmacokinetics

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

Doxorubicin in plasma

0.00

0 1

Courtesy of J Geschwind IA free doxorubicin IA DEB doxorubicin

2

Time (hrs)

3 4 IA Control DEB 450 400 350 300 250 200 150 100 50 0 0 100

Courtesy of J Geschwind Doxorubicin in tumor IA free doxorubicin IA DEB doxorubicin

200

Time (hrs)

300 400

Pharmakokinetic in human

IA Control DEB

Preliminary clinical results

Difficulties in evaluating Preliminary clinical results

70% 60% 50% 40% 30% 20% 10% 0% 64% DEB** Response rate

** Varela M, Llovet J, Bruix J, J Hepatol 2007

Difficulties in evaluating Preliminary clinical results

70% 60% 50% 40% 30% 20% 10% 0% 35-37% 20% 44% Conventional TACE * DEB** RECIST EASL

* Lo C, Hepatology 2002 & Llovet JM, Lancet 2002 ** Varela M, Llovet J, Bruix J, J Hepatol 2007

Difficulties in evaluating Preliminary clinical results

RECIST

80 70 60 50 40 30 20 10 0 Partial Response Stable Disease Progressive Disease 3 months 6 months

71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments

(Malagari K, Abdominal imaging 2007)

71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments

Best Overall response : 53/71 = 74%

(Malagari K, Abdominal imaging 2007)

71 patients HCC (3-10cm) Child A (27), Child B (44) EASL (intention to treat) CR : 15.5% OR : 66.2% to 85.5% across the 4 treatments Survival 97.5% @ 12 months 91.1% @ 18 months 88.2% @ 30 months

(Malagari K, Abdominal imaging 2007)

4ml of 300-500  m DEB

+

100 mg doxorubicin • Neuroendocrine liver metastases • • • • • Morphologic RECIST @ 1 months

Partial response Minor response Stable disease Progressive disease

8/20 (40%) 2/20 (10%) 5/20 (25%) 1/20 (5%)

4ml of 300-500  m DEB

+

100 mg doxorubicin • Neuroendocrine liver metastases • • • • • Morphologic RECIST @ 1 months - 3 months

Partial response Minor response Stable disease Progressive disease

8/20 (40%) 2/20 (10%) 5/20 (25%) 1/20 (5%) 16/20 (80%) 2/20 (10%) 1/20 (5%) 1/20 (5%)

DEB preliminary results

4ml of 300-500  m DEB

+

100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months - 3 months • • •

Partial response Minor response Stable disease

8/20 (40%) 2/20 (10%) 5/20 (25%) 16/20 (80%) 2/20 (10%) 1/20 (5%) •

Progressive disease

1/20 (5%) 1/20 (5%) 20% peripheral liver necrosis associate with more post-procedural pain

(In press, JVIR)

DEB preliminary results

4ml of 300-500  m DEB

+

100 mg doxorubicin • Neuroendocrine liver metastases • Morphologic RECIST @ 1 months - 3 months • • •

Partial response Minor response Stable disease

8/20 (40%) 2/20 (10%) 5/20 (25%) 16/20 (80%) 2/20 (10%) 1/20 (5%) •

Progressive disease

1/20 (5%) 1/20 (5%) Lipiodol TACE PR: 41% MR: 33% SD: 15%

(A Roche & T de Baere; Europ Radiol 2003)

Irinotecan DEB Proof-of-Concept Study: Design   Evaluation of TACE in a rat liver metastasis model Model: Diffuse liver metastasis is induced by injecting 4x10 6 CC531-lac-Z rat colorectal carcinoma cells into the portal vein of male Wag/Rij rats  Objectives:  Compare embolization only to Irinotecan (low and high dose)  Doses chosen: 20 mg/kg and 30 mg/kg Irinotecan  Determine the effectiveness in terms   reduction in tumor cell load liver weight

Irinotecan DEB Proof-of-Concept Study: Preliminary Data • Preliminary results presented at AACR (Washington, April 06) 140 Tumour cell number Liver weight 120 100 80 p=0.05

p=0.07

60 40 20 0 DC Bead No Drug

Chemoemebolization of rat colorectal liver metastases with drug eluting beads loaded with irinotecan or doxorubicin. Clin Exp Metastasi 2008. Eyol E et al

DC beads and colorectal metastases

62 patients with CRC metastases At least 2 previous lines of chemotherapy Tumor burden < 70% Bilirubin w X2 normal value 138 courses of TACE with Irinotecan-DEB 2ml DEB 100-300 & 2ml 300-500 / 200 mg irinotecan 1-3 courses TACE every 3/4 weeks 55 right, 47 left, 39 right+left 48 X 2ml & 90 X 4ml

(Aliberti C, Fiorentini G, Cancer Research 2006) (Aliberti C, Fiorentini G, CIRSE 2008)

DC beads and colorectal metastases

62 patients with CRC metastases Med Follow-up = 15.4 months Response EASL = 85% RECIST = 78% @ 3 months Improvement of QOL = 90% during 3-12 months (med= 6.5) Survival Median survival not reached at 22 months Median free of symptioms 5.3 months Median to new chemo 6.3 months

(Aliberti C, Fiorentini G, Cancer Research 2006) (Aliberti C, Fiorentini G, CIRSE 2008)

Combined treatment

Angiogram Post RF of colorectal mets CT immediately post DEB injection CT at 6 weeks (R Lencioni, J Hepatology 2008)

DEB future

 Randomization DEB / Conventional  Precision V in Europe (completed)  MRI at 3m and 6m  Efficacy (treatment response).  European Association for the Study of the Liver (EASL)  Response Evaluation Criteria in Solid Tumours (RECIST)  SURVIVAL ?

 Colo-rectal cancer  Hudge population, numerous drugs in 1st to 3rd lines

Drug Eluting Beads



Reproducibility > Lipiodol



Low systemic level drug



Increase in efficacy



Decrease toxicity



Encouraging preliminary results



combination with so called targeted therapy ?



sorafenib, sunitinib, …