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Dynamic CT imaging (DCE-CT) in the anti-angiogenic response in Metastatic Renal Cell Carcinoma Prof. C A Cuenod, L Fournier, G Frija Laboratoire de Recherche.

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Presentation on theme: "Dynamic CT imaging (DCE-CT) in the anti-angiogenic response in Metastatic Renal Cell Carcinoma Prof. C A Cuenod, L Fournier, G Frija Laboratoire de Recherche."— Presentation transcript:

1 Dynamic CT imaging (DCE-CT) in the anti-angiogenic response in Metastatic Renal Cell Carcinoma Prof. C A Cuenod, L Fournier, G Frija Laboratoire de Recherche en Imagerie, Université Paris R Descartes. Radiology, Hôpital Européen Georges Pompidou, Paris ESUR Munich 2008

2 Tumour angiogenesis is a major topic in oncology 1971 Judah Folkman New England Journal of Medecine

3 Tumour neo-angiogenesis « Under the stimuli of malignant cells, the endothelial cells build a complete new network of capillaries » R Jain

4 Tumor angiogenesis EGF IGF-1 PDGF IL-8 bFGF Hypoxia COX-2 NO Oncogenes VEGF release Binding and activation of VEGF receptor H2O2H2O2 ProliferationSurvivalMigration Angiogenesis Permeability Increased expression (MMP, tPA, uPA, uPAr, eNOS, etc.) – P P– Folkman. NEJM 1971;285: Growth Factors

5 Sunitinib /Sutent Sorafenib / Nexavar Sorafenib Avastin RAD001 Patel Br J Cancer 2006 Anti-angiogenic treatment Endothelial Cell membrane

6 Surrogate markers reflecting treatment efficacy Reference = tumour size RECIST RECIST = Response Evaluation Criteria in Solid Tumors Therasse P. et al, J Natl Cancer Inst 2000;92: Functional imaging = measuring tumour vascularisation, target of anti-angiogenic drugs Reference = tumour size RECIST RECIST = Response Evaluation Criteria in Solid Tumors Therasse P. et al, J Natl Cancer Inst 2000;92: Functional imaging = measuring tumour vascularisation, target of anti-angiogenic drugs

7 Therasse P. et al, J Natl Cancer Inst 2000;92: Measuring (and adding) the longest diameters in targets RECIST = Response Evaluation Criteria in Solid Tumors

8 Lésions cibles 10 mm Lésions non cibles Nouvelles lésions Réponse 30% de la taille des lésions cibles StabilitéProgression 20% de la taille des lésions cibles OU des lésions non cibles OU nouvelle lésion

9 % variation of the sum Treatment cycles -30% +20% Progressive disease PD Stable Disease SD Partial Response PR 0 BASELINE

10 % variation of the sum Treatment cycles -30% +20% Progressive disease PD +20% Time to progression

11 Groupe sous traitement Groupe placebo Size variation in RCC under anti-angiogenic treatment vs. placebo Placebo Treatment

12 DCE-Imaging Functional evaluation

13 90 s postcontrast precontrast

14 Regions of interest (ROIs) over time

15 Patients Patients: Metastatic RCC April 2004-May 2006 Clinical trials: Sorafenib / Nexavar® vs. placebo Sunitinib / Sutent® vs. interferon

16 Acquisition 1- First exam before IV (low dose) (for target selection) => Functional target selection 2 - Dynamic Acquisition low dose: 80 mL contrast = 3x30s-breathholds, 1 image/s for 90 s 3 - Standard whole-body acquisition (+40mL) Total injection 120 mL (Xenetix®, 350 mg I/mL) 80kV Radiation dose supplement 200/2000 mGy/cm

17 Choice of functional target Size > 2 cm Minimal movements Retroperitoneum > mediastinum > lung Not liver or bone (medullary)

18 Results

19 ARTERY (Arterial Input Function) Tissue response

20 IN OUT Main microvascular parameters Regional blood perfusion (ml/min/100ml) Fractional Blood volume (%) Permeability x surface (ml/min/100ml) Dependent on tracer Fractional intersitial volume (%)

21 Main microvascular parameters IN OUT FT (ml/min/100ml) BV (%) PS (ml/min/100ml) Dependent on tracer Ve (%) Mean Transit time TTM = VB/FT

22 Artere q artere 1 Capillaire Q cap 2 M odélisation Analyse compartimentale k(2,3) q Tumeur Interstitium q inter 3 k(3,2) k(2,1) k(0,2)

23 Can we detect an effect on tumour vessels after a single cycle of treatment by anti- angiogenic drugs?

24 Variable* (%) Placebo N=8 Interferon N=5 Anti- angiogenic N=25 Tissue Blood flow (ml/min/100ml) [-27.3; [-18.8; 0.8] -50 [-72;-3] Tissue Blood volume (%) -4.2 [-22.0; 5.6] 2.0 [-5.5; 18.0] -51 [-67;-24] Mean transit time (s) 17.0 [7.4; 28.5] -2.4 [-10.2; 16.6] 5 [-22;73] Permeability surface area product (mL/min/100ml) [-47.4;-14.5] 16.4 [-11.9;20.9] -34* [-83 ; 8] Sum of longest diameters (mm) 5.5 [-1.0; 11.8] -3.8 [-16.5; -0.7] -17 [-29.0; -7.0] * Significant for Nexavar, not Sutent

25 Variable* (%) Placebo N=8 Interferon N=5 Anti- angiogenic N=25 Blood flow (ml/min/100ml) [-27.3; [-18.8; 0.8] -50 [-72;-3] Blood volume (%) -4.2 [-22.0; 5.6] 2.0 [-5.5; 18.0] -51 [-67;-24] Mean transit time (s) 17.0 [7.4; 28.5] -2.4 [-10.2; 16.6] 5 [-22;73] Permeability surface area product (mL/min/100ml) [-47.4;-14.5] 16.4 [-11.9;20.9] -34 [-83 ; 8] Sum of longest diameters (mm) 5.5 [-1.0; 11.8] -3.8 [-16.5; -0.7] -17 [-29.0; -7.0]

26 RCC metastasis under anti-angiogenic therapy: Good responder 16/06/05 BF : 18 01/12/04 BF : 130

27 12/04/05 BF : /01/05 BF : 250 RCC metastasis under anti-angiogenic therapy: Poor responder

28 05/ Size variation (%) DCE-CT vs morphology Blood Flow maps BaselineCycle 1 – 6 weeksCycle 4 – 30 weeks

29 Can baseline parameters as measured by functional imaging predict future tumour response?

30 Variable (%) Response N=10 Stable N=20 Progression N=2 P (S vs. R) Blood flow (mL/min/100ml) [130.3; 453.5] [74.1; 224.3] [162.5; 218.5] 0.04 Blood volume (mL/min/100ml) 15.5 [9.0; 24.5] 8.2 [5.6; 14.9] 9.6 [9.2; 10.1] 0.02 Mean transit time (s) 5.6 [3.5; 9.5] 9.0 [5.0; 13.6] 5.4 [5.1; 5.7] 0.07 Surface permeability product (mL/min/100ml) 9.9 [9.1; 21.1] 7.3 [6.0; 13.2] 9.0 [8.7; 9.3] 0.12 Sum of longest diameters (mm) [76.0 ; 252.0] [91.0 ; 198.5] 73.0 [50.0 ; 96.0] 0.18

31 Limits – clinical study Difficulties 50% of patient data incomplete or data analysis failed 102 patients in clinical trial 51 patients successful DCE-CT

32 DCE analysis failed CT not injected (allergy, kidney failure) (N = 5, 10%) CT not performed at our institution (N = 23, 45%) Baseline perfusion acquisition not performed (N = 10, 18%) Failure of modeling: movement, SNR (N = 13, 23%)

33 AIF

34 Limits – clinical study Inter-investigator reproducibility 2 investigators

35 Blood flow – investigator #1 Blood flow – investigator #2 R = 0.91 R² = 0.82

36 PS – investigator #1 PS – investigator #2 R = 0.45 R² = 0.20

37 Clinical study: conclusions DCE-CT can be used in a clinical context Difficulties to implement the technique organisation +++ motion (lung metastases)

38 IRM vs CT

39 Critères dynamiques Profil « malignité » …..« bénignité » Kuhl Eur. Radiol.2000;10: % des K 34 % des K 9% des K 5% des L.Bénignes 12% des LB 83% des LB Kuhl Eur. Radiol.2000;10:46-58

40

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42 Remarques techniques

43 Correction des mouvements respiratoires

44 Arterial input function True individual AIF Mean AIF Synthetic AIF

45 1 image/ 10 sec1 image / 1 min Peak is missed Slope Steady state

46 Tumor treatment Tumor volume Weeks Hours/Days function


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