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
TACE of Colorectal Cancer Liver Metastases
pts.
line
drugs
embx.
30
SL
C/D/M
collagen
n.r.
n.r.
Leichman `99 31
FL
C/D/M
collagen
29
8
14
Salman `02
24
SL
FU/INF
PVA
21
n.r.
11
Müller ´03
66
FSL
FU/Mel IO/GF
43
8
8
Hong ´09
21
FSL
C/D/M
n.r.
n.r.
8
Vogl `09
463
SL
M/Gem/I IO/DSM
15*
n.r.
14
Albert `10
121
SL
C/D/M
3
9
Tellez `98
PVA
IO/PVA
ORR(%) PFSV(mo)
2*
Drugs: C= Cisplatin; D=Doxorubicin; M=Mitomycin C; FU=5-FU;
INF=Interferon; Mel=Melphalan; Gem= Gemcitabin, I=Irinotecan;
mOSV (mo)
9
*RECIST
TACE of Colorectal Cancer Liver Metastases
pts.
line
drugs
embx.
30
SL
C/D/M
collagen
n.r.
n.r.
Leichman `99 31
FL
C/D/M
collagen
29
8
Tellez `98
ORR(%) PFSV(mo)
mOSV (mo)
9
14
Salman
24 SL of local
FU/INF
PVA
21
n.r. HAI studies
11
-No`02
improvement
oRR compared
to historical
Müller ´03
66
FSL
FU/Mel IO/GF
43
8
8
-No comparative studies to systemic treatment in SL setting
Hong ´09
21
FSL
C/D/M
PVA
n.r.
n.r.
8
VoglT.P.
`09 Pwint
463
SL roleM/Gem/I
IO/DSM 15* in liver
n.r. metastases
14from
: „…the
of chemoembolization
CRC
(Semin Oncol
Albert
`10has not
121 been
SL established.“
C/D/M IO/PVA
2* 2010;37:149-159)
3
9
-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
Regional Advantage of i.a. Irinotecan
Rart =
CL
QA (1 - Er )
Rart : advantage of IA vs IV
CL : total body clearance
QA : arterial flow
Er :extraction ratio /1st pass
Regional Advantage of i.a. Irinotecan
Rart =
CL
QA (1 - Er )
Rart : advantage of IA vs IV
CL : total body clearance
QA : arterial flow
Er :extraction ratio /1st pass
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
0.3-0.5
DOXO
45-50
-
DC Beads +
Irinotecan®
PVA macromere
backbone
Hydrated Beads
Grafting
point
DC Bead before irinotecan loading
Drug-loaded Beads
Irt+
DC Bead after irinotecan loading
SO3-
SO3-
Irt+
SO3-
SO3SO3-
Sulfonated
polymer chain
backbone
Irinotecan
Solution
SO3SO3-
SO3SO3-
SO3-
SO3-
SO3
SO3-
Irt+
Irt+
SO3-
Irt+
Bulk
Hydration shell
associated with PVA and (non-bound)
water
ionic groups
SO3-
Irt+
SO3-
Irt+
SO3-
Irt+
Irt+
SO3-
SO3SO3-
SO3SO3-
Irt+
SO3SO3-
-
SO3-
Irt+
Irt+
SO3-
Irt+
Interaction of irinotecan (Irt+) with SO3- groups
by an ion-exchange process
displaces water from the hydration shells
Loading procedure of DEBIRI
 1 Vial 2 cc Beads + 6 cc
saline
 aspirate saline
Loading procedure of DEBIRI
 1 Vial 2 cc Beads + 6 cc
saline
 aspirate saline
 add 100 mg Irinotecan
(5 cc Campto®, Pfizer)
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)
Irinotecan
eluting Beads
 Precisely calibrated size
 Loading by ion exchange
50 mg I/cc Beads
100 mg / Vial
in vitro
 Uptake (3h) 93%
 Release (1w) 100%
 t75%
66 min
Jordan et al. 2010 JVIR 21:1084-90
600
Irinotecan: Irinotecan Beads (20-60mg/m2)
Plasma Concentration (ng/ml)
70-150 µm
100-300µm
300-500µm
Irinotecan 50mg/m2 IV*
500
400
300
200
100
0
0
5
10
15
20
25
Time (hrs)
Forni et al Cancer Res. 2008
Will Beads enter colorectal
cancer metastases?
Will Beads enter colorectal
cancer metastases?
Yes!
100 mg Irinotecan loaded in 2
cc Beads 70-150 µm + 5 cc CM
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
100-300 µm
 35-200 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
Inclusion criteria
 Unresectable liver metastases
 Progression after standard systemic
treatment or intolerable side effects
 Approved by the local ethics committee
 Patients informed consent
Case # 1 DC Beads CR/PR
Age/sex
LMts
Syst. Trx.
58y / f
10/08
11/05-2/10
TACE
Irinotc
DEB
EASL
RECIST
SV
Case # 1 DC Beads 100-300 µm CR/PR
Age/sex
LMts
Syst. Trx.
TACE
Irinotc
DEB
58y / f
10/08
11/05-2/10
11.02.10
23.02.10
100 mg
100 mg
2 cc
2 cc
EASL
RECIST
2 cc Beads 100-300 µm
100 mg Irinotecan
SV
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
11.02.10
23.02.10
100 mg
100 mg
2 cc
2 cc
PR
(70%)
PR
(3mo)
al.
baseline
2 months
3 months
Results DEBIRI 100-300µm
DC Beads
CR
PR
SD
PD
3-Mo EASL
23%
41%
18%
18%
3-Mo RECIST
0
6%
71%
23%
6-Mo RECIST
0
0
43%
57%
median TTP
5 mo
Median OSV
9 mo
Pain
Nausea/vomiting
Grade 1
14%
Grade 1
50%
Grade 2
23%
Grade 2
37%
Grade 3
35%
Grade 3
13%
Grade 4
28%
Grade 4
0
Hypertension
22%
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
09.03.10
30.03.10
18.05.10
100mg
100mg
100mg
2.0 cc
2.0 cc
2.0 cc
PR
(80%
-20%)
SD
(4 mo)
al
22.2.10
22.4.10
no complete necrosis
9.6.10
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
200 mg
50mg
38 mg
50mg
PD
PD
8
05/06/08
11/09/08
06/10/08
18/12/08
Potential Advantages
DC Beads® M1 (70-150 µm)
 Deep penetration into tumor vascular bed
 Shrinking after loading to 65-120 µm
 Preventing collateral supply
 Complete necrosis
DC Beads M1 (70-150 µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
EASL
RECIST
SV
(70-150 µm)
Dynaperfusion
CT
hypovascular tumor
28/09/10
DC Beads M1 (70-150 µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
EASL
RECIST
(70-150 µm)
1 cc M1
2 cc M1
During/after TACE
28/09/10
29/09/10
SV
DC Beads M1 (70-150 µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
EASL
RECIST
SV
(70-150 µm)
1 cc M1
During/after TACE
28/09/10
2 cc M1
intensive uptake of Beads/CM
29/09/10
DC Beads M1 (70-150 µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
EASL
RECIST
SV
(70-150 µm)
+1d
28/09/10
29/09/10
+3d
01/1010
01/1010
10/10
Intensive uptake of DC Beads® M1: complete necrosis of hypovascular tumor
DC Beads M1 (70-150 µm)
Age/sex
LMts
Chth
TACE
Irinotc
M1 Beads
78 Y / m
9/09
9/0-8/10
28/09/10
100 mg
2cc
EASL
(70-150 µm)
+1d
28/09/10
29/09/10
+3d
01/1010
01/1010
10/10
70-150 µm Beads have the potential of
deep penetration into tumor vascular bed
inducing complete necrosis
even in hypovascular tumors
RECIST
SV
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
70-150 µm
 80-200 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
Patients Characteristics
Patients
8
age
50-82 (71)
m/f
6/2
prior syst. Trx.
7/8
prior syst. Irinotecan Trx.
7/8
Liver involvement <25%/25-50%/>50%
4/2/2
Extrahepatic Mts.
4/8
Indication for DEBIRI: PD/side effects
6/2
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 (RECIST) @3Mo. 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
0
grade 1
grade 2
grade 3
grade 4
Preliminary comparison Beads
100-300µm vs. 70-150µm M1
Beads 100-300 µm
Beads 70-150 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%
Preliminary Conclusions
 High-grade uptake of
M1/CM is associated
with complete tumor
necrosis.
Preliminary Conclusions
 Low-grade uptake of
M1/CM is associated
with incomplete
necrosis.
Preliminary Conclusions
 High-grade uptake of
M1/CM occurs in
metastases with
hypervascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM occurs in
metastases with
hypervascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM occurs in
metastases with
hypervascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM occurs in
metastases with
hypervascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM also occurs in
metastases with lowgrade vascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM also occurs in
metastases with lowgrade vascularization.
Preliminary Conclusions
 High-grade uptake of
M1/CM also occurs in
metastases with lowgrade vascularization.
Preliminary Conclusions
 Singular arterial supply
of metastases is
associated with highgrade uptake of
M1/CM.
S4
Preliminary Conclusions
 Singular arterial supply
of metastases is
associated with highgrade uptake of
M1/CM.
S4
Preliminary Conclusions
 Multiple arterial supply
of metastases is
associated with lowgrade uptake of
M1/CM.
Preliminary Conclusions
 Multiple arterial supply
of metastases is
associated with lowgrade uptake of
M1/CM.
Preliminary Conclusions
 Multiple arterial supply
of metastases is
associated with lowgrade uptake of
M1/CM.
Preliminary Conclusions
 Multiple arterial supply
of metastases is
associated with lowgrade uptake of
M1/CM.
Preliminary Conclusions
 Multiple arterial supply
of metastases is
associated with lowgrade uptake of
M1/CM.
S4
multiple feeders
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.
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)
Thank You for Your
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