1. Irinotecan eluting DC Bead® M1 for Treatment of Colorectal Liver Metastases: Preliminary Results
Peter Huppert
Department of Diagnostic and Interventional Radiology
Klinikum Darmstadt
Academic Teaching Hospital
Universities Heidelberg/Mannheim & Frankfurt
Germany
GEST 2011

2. TACE of Colorectal Cancer Liver Metastases
pts line drugs embx. ORR(%) PFSV(mo) mOSV (mo)
Tellez ` SL C/D/M collagen n.r. n.r
Leichman ` FL C/D/M collagen
Salman ` SL FU/INF PVA n.r
Müller ´ FSL FU/Mel IO/GF
Hong ´ FSL C/D/M PVA n.r. n.r
Vogl ` SL M/Gem/I IO/DSM 15* n.r
Albert ` SL C/D/M IO/PVA *
Drugs: C= Cisplatin; D=Doxorubicin; M=Mitomycin C; FU=5-FU; INF=Interferon; Mel=Melphalan; Gem= Gemcitabin, I=Irinotecan;
*RECIST

3. TACE of Colorectal Cancer Liver Metastases
pts line drugs embx. ORR(%) PFSV(mo) mOSV (mo)
Tellez ` SL C/D/M collagen n.r. n.r
Leichman ` FL C/D/M collagen
Salman ` SL FU/INF PVA n.r
Müller ´ FSL FU/Mel IO/GF
Hong ´ FSL C/D/M PVA n.r. n.r
Vogl ` SL M/Gem/I IO/DSM 15* n.r
Albert ` SL C/D/M IO/PVA *
No improvement of local oRR compared to historical HAI studies
No comparative studies to systemic treatment in SL setting
T.P. Pwint : „…the role of chemoembolization in liver metastases from CRC has not been established.“ (Semin Oncol 2010;37: )
rationale for Irinotecan eluting Microspheres
Drugs: C= Cisplatin; D=Doxorubicin; M=Mitomycin C; FU=5-FU; INF=Interferon; Mel=Melphalan; Gem= Gemcitabin, I=Irinotecan;
*RECIST

4. Regional Advantage of i.a. IrinotecanCL
Rart =
QA (1 - Er )
Rart : advantage of IA vs IV CL : total body clearance
QA : arterial flow
Er :extraction ratio /1st pass

5. Regional Advantage of i.a. IrinotecanCL
Rart =
QA (1 - Er )
Drug
% Liver extraction
Clearance TB (l/min)
5-FU
22-45
2-5
FUDR
69-92
5-15
IRINOTECAN
38-72
9-25
MITO-C
7-18
3-5
CDDP
8-50
DOXO
45-50 -
Rart : advantage of IA vs IV CL : total body clearance
QA : arterial flow
Er :extraction ratio /1st pass

6. DC Beads + Irinotecan® Irt+ Hydration shell associated with PVA and
DC Bead before irinotecan loading
SO3-
Irt+
Hydration shell
associated with PVA and
ionic groups
Interaction of irinotecan (Irt+) with SO3- groups
by an ion-exchange process
displaces water from the hydration shells
Irinotecan
Solution
Hydrated Beads
Bulk
(non-bound)
water
PVA macromere
backbone
Sulfonated
polymer chain
Grafting
point
Drug-loaded Beads
DC Bead after irinotecan loading

7. Loading procedure of DEBIRI
1 Vial 2 cc Beads + 6 cc saline
aspirate saline

8. Loading procedure of DEBIRI
1 Vial 2 cc Beads + 6 cc saline
aspirate saline
add 100 mg Irinotecan (5 cc Campto®, Pfizer)

9. Loading procedure of DEBIRI
1 Vial 2 cc Beads + 6 cc saline
aspirate saline
add 100 mg Irinotecan (5 cc Campto®, Pfizer)
loading time 120 min
aspirate excess
add CM (5 cc plus X) and water (X cc)

10. Irinotecan eluting Beads
Precisely calibrated size µm µm µm
Loading by ion exchange 50 mg I/cc Beads 100 mg / Vial in vitro
Uptake (3h) %
Release (1w) 100%
t75% min
Forni et al Cancer Res. 2008
Jordan et al JVIR 21:

11. Will Beads enter colorectal cancer metastases?

12. Will Beads enter colorectal cancer metastases?

13. Yes!
100 mg Irinotecan loaded in 2 cc Beads µm + 5 cc CM

14. Protocol (12 Patients, 31 TACE)
Prospective Single Center Single Arm Study Ph I/II Irinotecan eluting DC Beads TACE in CRC-LMts. (1-9 / 2010)
Protocol (12 Patients, 31 TACE)
100 mg Irinotecan/ 2cc Beads
mg (mean: 178 mg) Irinotecan/trx.
sel. injection via 3 F micro-cath. if possible
endpoint: stopflow*
i.v. Kevatril®, Dexam., Morphine , Metamizol
TACE/pt. mean: 2.5, range: 2-3
Trx.interval mean: 4.9 w, range: 2-12 w
study endpoints: response (EASL, RECIST), TTP, overall SV, side effects µm

15. Inclusion criteria Unresectable liver metastases
Progression after standard systemic treatment or intolerable side effects
Approved by the local ethics committee
Patients informed consent

16. Case # 1 DC Beads CR/PR Age/sex LMts Syst. Trx. TACE Irinotc DEB EASL
RECIST SV
58y / f
10/08
11/05-2/10

17. Case # 1 DC Beads 100-300 µm CR/PR
Age/sex
LMts
Syst. Trx.
TACE
Irinotc
DEB
EASL
RECIST SV
58y / f
10/08
11/05-2/10
100 mg
2 cc
2 cc Beads µm
100 mg Irinotecan

18. Case # 1 DC Beads 100-300µm CR/PR
Age/sex
LMts
Syst. Trx.
TACE
Irinotc
DEB
EASL
RECIST SV
58y / f
10/08
11/05-2/10
100 mg
2 cc
PR (70%)
PR (3mo)
al.
baseline
2 months
3 months

19. Results DEBIRI 100-300µm DC Beads CR PR SD PD 3-Mo EASL 23% 41% 18%
3-Mo RECIST 6%
71%
6-Mo RECIST
43%
57%
median TTP
5 mo
Median OSV
9 mo
Pain
Nausea/vomiting
Hypertension
Grade %
Grade %
22%
Grade %
Grade %
Grade %
Grade %
Grade %
Grade

20. Case # 2 DC Beads 100-300µm Recurrency
Age/sex
LMts
Syst. Trx.
TACE
Irinotc
DEB
EASL
RECIST SV
72 Y / m
3/07
4/07-2/10
100mg
2.0 cc
PR (80%
-20%) SD
(4 mo) al
9.6.10
no complete necrosis

21. Case # 3 DC Beads 100-300µm Recurrency ++
Age/sex
LMts
Chth
TACE
Irinotc
HeSph
EASL
RECIST SV
64 Y / m
9/07
9/07-5/08
02/07/08
05/08/08
10/09/08
200 mg
150 mg
50mg
38 mg PD 8
05/06/ /09/ /10/ /12/08

22. Potential Advantages DC Beads® M1 (70-150 µm)
Deep penetration into tumor vascular bed
Shrinking after loading to µm
Preventing collateral supply
Complete necrosis

23. DC Beads M1 (70-150 µm) Dyna-perfusion CT hypovascular tumor 28/09/10
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
EASL
RECIST SV
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
( µm)
Dyna-perfusion CT
hypovascular tumor
28/09/10

24. DC Beads M1 (70-150 µm) 2 cc M1 1 cc M1 During/after TACE
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
EASL
RECIST SV
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
( µm)
2 cc M1
1 cc M1
During/after TACE
28/09/ /09/10

25. DC Beads M1 (70-150 µm) 2 cc M1 1 cc M1 intensive uptake of Beads/CM
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
EASL
RECIST SV
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
( µm)
2 cc M1
1 cc M1
intensive uptake of Beads/CM
During/after TACE
28/09/ /09/10

26. DC Beads M1 ( µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
EASL
RECIST SV
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
( µm)
+1d
+3d
01/1010
28/09/10
29/09/10
01/1010
10/10
Intensive uptake of DC Beads® M1: complete necrosis of hypovascular tumor

27. DC Beads M1 ( µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
EASL
RECIST SV
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
( µm)
+1d
+3d
01/1010
28/09/10
29/09/10
01/1010
10/10
µm Beads have the potential of deep penetration into tumor vascular bed
inducing complete necrosis
even in hypovascular tumors

28. Protocol M1 (8 Patients, 18 TACE)
Prospective Single Center Single Arm Study Ph I/II Irinotecan eluting DC Beads M1 TACE in CRC-LMts.
Protocol M1 (8 Patients, 18 TACE)
100 mg Irinotecan/ 2cc Beads
mg (mean: 118 mg) Irinotecan/trx.
sel. injection via 3 F micro-cath. if possible
endpoint: stopflow*
i.v. Kevatril®, Dexam., Morphine , Metamizol
TACE/pt. mean: 2.5, range: 2-3
Trx.interval mean: 6.1 w, range: 2-16 w
study endpoints: uptake of Beads/CM response (EASL, RECIST), TTP, overall SV, side effects µm

29. Patients Characteristics8
age
50-82 (71)
m/f
6/2
prior syst. Trx.
7/8
prior syst. Irinotecan Trx.
Liver involvement <25%/25-50%/>50%
4/2/2
Extrahepatic Mts.
4/8
Indication for DEBIRI: PD/side effects

30. Results DEBIRI M1 Uptake of Beads/CM (+1d) grade 0-4 (1.8)
Necrosis (%)
50%-100% (77%)
First response (EASL)
CR 4/8; PR 2/8; PD 2/8
Best response
SD 6/8; PD 2/8
TTP (median)
1mo-5mo (3.0mo)
Extrahepatic PD
2/8
Side effects grade 1/2/3
5/2/1
Complications
grade 1
grade 2
grade 3
grade 4

31. Preliminary comparison Beads 100-300µm vs. 70-150µm M1
Beads µm (M1)
Tumor necrosis
56%
77%
first response (EASL)
CR 23% / PR 41%
CR 50% / PR 25%
Side effects grade 1/2/3
50/37/13%
62/25/13%

32. Preliminary Conclusions
High-grade uptake of M1/CM is associated with complete tumor necrosis.

33. Preliminary Conclusions
Low-grade uptake of M1/CM is associated with incomplete necrosis.

34. Preliminary Conclusions
High-grade uptake of M1/CM occurs in metastases with hypervascularization.

35. Preliminary Conclusions
High-grade uptake of M1/CM occurs in metastases with hypervascularization.

36. Preliminary Conclusions
High-grade uptake of M1/CM occurs in metastases with hypervascularization.

37. Preliminary Conclusions
High-grade uptake of M1/CM occurs in metastases with hypervascularization.

38. Preliminary Conclusions
High-grade uptake of M1/CM also occurs in metastases with low- grade vascularization.

39. Preliminary Conclusions
High-grade uptake of M1/CM also occurs in metastases with low- grade vascularization.

40. Preliminary Conclusions
High-grade uptake of M1/CM also occurs in metastases with low- grade vascularization.

41. Preliminary Conclusions
Singular arterial supply of metastases is associated with high- grade uptake of M1/CM. S4

42. Preliminary Conclusions
Singular arterial supply of metastases is associated with high- grade uptake of M1/CM. S4

43. Preliminary Conclusions
Multiple arterial supply of metastases is associated with low- grade uptake of M1/CM.

44. Preliminary Conclusions
Multiple arterial supply of metastases is associated with low- grade uptake of M1/CM.

45. Preliminary Conclusions
Multiple arterial supply of metastases is associated with low- grade uptake of M1/CM.

46. Preliminary Conclusions
Multiple arterial supply of metastases is associated with low- grade uptake of M1/CM.

47. Preliminary Conclusions
Multiple arterial supply of metastases is associated with low- grade uptake of M1/CM. S4
multiple feeders

48. Preliminary Conclusions
Preliminary results are encuraging in terms of uptake of Beads® and local tumor response.
Treatment intervals are shorter compared to TACE in HCC.
Median TTP in a salvage situation was 3.0 months.
No complications, tolerable side effects.
Continuation of the studies necessary.

49. Drug eluting Microspheres in CRC Mts.- Questions to answer:
Selective vs. non-selective TACE?
Optimal treatment interval 2…..6 weeks?
Combination with systemic biological Trx. (activation of VEGF and HIF-1)

50. Thank You for Your Attention!

51. Submit your abstracts by February 11, 2011!
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Submit your abstracts by February 11, 2011!