irinotecan eluting dc bead® m1 for treatment of colorectal liver metastases: preliminary results...

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?

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


28/09/10 29/09/10

Age/sex


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


28/09/10 29/09/10

Age/sex


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


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


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.


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


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


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


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


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


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

S4

multiple feeders


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 Attention!

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irinotecan eluting dc bead® m1 for treatment of colorectal liver metastases: preliminary results...

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