irinotecan eluting dc bead® m1 for treatment of colorectal liver metastases: preliminary results...
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Irinotecan eluting DC Bead® M1for Treatment of Colorectal Liver
Metastases:Preliminary Results
Peter HuppertDepartment of Diagnostic and Interventional Radiology
Klinikum DarmstadtAcademic Teaching Hospital
Universities Heidelberg/Mannheim & FrankfurtGermany
GEST 2011
TACE of Colorectal Cancer Liver Metastases
pts. line drugs embx. ORR(%)PFSV(mo) mOSV (mo)
Tellez `98 30 SL C/D/M collagen n.r. n.r. 9
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 PVA 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 IO/PVA 2* 3 9
Drugs: C= Cisplatin; D=Doxorubicin; M=Mitomycin C; FU=5-FU; INF=Interferon; Mel=Melphalan; Gem= Gemcitabin, I=Irinotecan;
*RECIST
TACE of Colorectal Cancer Liver Metastases
pts. line drugs embx. ORR(%)PFSV(mo) mOSV (mo)
Tellez `98 30 SL C/D/M collagen n.r. n.r. 9
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 PVA 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 IO/PVA 2* 3 9
Drugs: C= Cisplatin; D=Doxorubicin; M=Mitomycin C; FU=5-FU; INF=Interferon; Mel=Melphalan; Gem= Gemcitabin, I=Irinotecan;
*RECIST
-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;37:149-159)
-rationale for Irinotecan eluting Microspheres
Rart : advantage of IA vs IV
CL : total body clearance
QA : arterial flow Er :extraction ratio /1st pass
CL
Rart = QA (1 - Er )
Regional Advantage of i.a. IrinotecanRegional Advantage of i.a. Irinotecan
Rart : advantage of IA vs IV
CL : total body clearance
QA : arterial flow Er :extraction ratio /1st pass
CL
Rart = QA (1 - Er )
Regional Advantage of i.a. IrinotecanRegional Advantage of i.a. Irinotecan
DrugDrug% Liver % Liver
extractionextractionClearance Clearance TB (l/min)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 + DC Beads + IrinotecanIrinotecan®®
DC Bead before irinotecan loading
DC Bead after irinotecan loading
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 size70-150 µm100-300µm300-500µm
Loading by ion exchange50 mg I/cc Beads100 mg / Vial
in vitro
Uptake (3h) 93% Release (1w) 100% t75% 66 min
Jordan et al. 2010 JVIR 21:1084-90
0
100
200
300
400
500
600
0 5 10 15 20 25
Time (hrs)
Pla
sma
Co
nce
ntr
atio
n (
ng
/ml)
Irinotecan: Irinotecan Beads (20-60mg/m2)
Irinotecan 50mg/m2 IV*
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 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
100-300 µm
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/PRAge/sex
LMts
Syst. Trx.
TACE Irinotc
DEB EASL
RECIST
SV
58y / f 10/08
11/05-2/10
Case # 1 DC Beads 100-300 µm CR/PRAge/
sexLMt
sSyst. Trx.
TACE Irinotc
DEB EASL
RECIST
SV
58y / f 10/08
11/05-2/10
11.02.10
23.02.10
100 mg100 mg
2 cc2 cc
2 cc Beads 100-300 µm100 mg Irinotecan
Case # 1 DC Beads 100-300µm CR/PRAge/
sexLMt
sSyst. Trx.
TACE Irinotc
DEB EASL
RECIST
SV
58y / f 10/08
11/05-2/10
11.02.10
23.02.10
100 mg100 mg
2 cc2 cc
PR(70%
)
PR(3mo)
al.
3 months
2 months
baseline
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 moPain Nausea/
vomitingHypertension
Grade 1 14%
Grade 1 50%
22%
Grade 2 23%
Grade 2 37%
Grade 3 35%
Grade 3 13%
Grade 4 28%
Grade 4 0
Case # 2 DC Beads 100-300µm RecurrencyAge/
sexLMt
sSyst. Trx.
TACE Irinotc
DEB EASL
RECIST
SV
72 Y / m
3/07 4/07-2/10
09.03.1030.03.1018.05.10
100mg
100mg
100mg
2.0 cc2.0 cc2.0 cc
PR (80%
-20%)
SD(4 mo)
al
22.2.10
22.4.10
9.6.10
no complete necrosis
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 mg150 mg200 mg
50mg38 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)
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(70-150 µm)
Dyna-perfusion CT
hypovascular tumor
DC Beads M1 (70-150 µm)
28/09/10 29/09/10
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(70-150 µm)
1 cc M1
2 cc M1
During/after TACE
DC Beads M1 (70-150 µm)
28/09/10 29/09/10
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(70-150 µm)
1 cc M1
2 cc M1
During/after TACE intensive uptake of Beads/CM
DC Beads M1 (70-150 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(70-150 µm)
10/1028/09/10 29/09/10 01/1010 01/1010
Intensive uptake of DC Beads® M1: complete necrosis of hypovascular tumor
+3d+1d
DC Beads M1 (70-150 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(70-150 µm)
10/1028/09/10 29/09/10 01/1010 01/1010
+3d+1d
70-150 µm Beads have the potential of deep penetration into tumor vascular bed
inducing complete necrosiseven in hypovascular tumors
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 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
70-150 µm
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 M1Uptake 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 3 grade 4grade 2grade 1
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 low-grade vascularization.
Preliminary Conclusions
High-grade uptake of M1/CM also occurs in metastases with low-grade vascularization.
Preliminary Conclusions
High-grade uptake of M1/CM also occurs in metastases with low-grade vascularization.
Preliminary Conclusions
Singular arterial supply of metastases is associated with high-grade uptake of M1/CM. S4
Preliminary Conclusions
Singular arterial supply of metastases is associated with high-grade uptake of M1/CM. S4
Preliminary Conclusions
Multiple arterial supply of metastases is associated with low-grade uptake of M1/CM.
Preliminary Conclusions
Multiple arterial supply of metastases is associated with low-grade uptake of M1/CM.
Preliminary Conclusions
Multiple arterial supply of metastases is associated with low-grade uptake of M1/CM.
Preliminary Conclusions
Multiple arterial supply of metastases is associated with low-grade uptake of M1/CM.
Preliminary Conclusions
Multiple arterial supply of metastases is associated with low-grade 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)
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