Peter Huppert Department of Diagnostic and Interventional Radiology

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Presentation transcript:

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. 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 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 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 CL Rart = 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 CL 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 0.3-0.5 DOXO 45-50 - Rart : advantage of IA vs IV CL : total body clearance QA : arterial flow Er :extraction ratio /1st pass

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

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 70-150 µm 100-300µm 300-500µm Loading by ion exchange 50 mg I/cc Beads 100 mg / Vial in vitro Uptake (3h) 93% Release (1w) 100% t75% 66 min Forni et al Cancer Res. 2008 Jordan et al. 2010 JVIR 21:1084-90

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

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 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/PR Age/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/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 2 cc 2 cc Beads 100-300 µm 100 mg Irinotecan

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 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% 3-Mo RECIST 6% 71% 6-Mo RECIST 43% 57% median TTP 5 mo Median OSV 9 mo Pain Nausea/vomiting Hypertension 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 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 2.0 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 mg 150 mg 50mg 38 mg 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) 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 (70-150 µm) Dyna-perfusion CT hypovascular tumor 28/09/10

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 (70-150 µm) 2 cc M1 1 cc M1 During/after TACE 28/09/10 29/09/10

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 (70-150 µm) 2 cc M1 1 cc M1 intensive uptake of Beads/CM During/after TACE 28/09/10 29/09/10

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) +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

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) +1d +3d 01/1010 28/09/10 29/09/10 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

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 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 8 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

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 grade 1 grade 2 grade 3 grade 4

Preliminary comparison Beads 100-300µm vs. 70-150µm M1 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)

Thank You for Your Attention!

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