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 Growth Factors Angiogenesis EGF IGF-1 PDGF IL-8
bFGF
Hypoxia 
COX-2 
NO 
Oncogenes 
VEGF release
Binding and activation
of VEGF receptor
H2O2
Proliferation
Survival
Migration
Angiogenesis
Permeability
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
– P P–
Growth Factors
Folkman. NEJM 1971;285:

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

6. Surrogate markers reflecting treatment efficacy
Reference = tumour size
RECIST = Response Evaluation Criteria in Solid Tumors
Therasse P. et al, J Natl Cancer Inst 2000;92:205-16
Functional imaging = measuring tumour vascularisation, target of anti-angiogenic drugs

7. RECIST = Response Evaluation Criteria in Solid Tumors
Therasse P. et al, J Natl Cancer Inst 2000;92:205-16
Measuring (and adding) the longest diameters in targets

8. Lésions non cibles Nouvelles lésions Réponse Stabilité Progression
Lésions cibles
 10 mm
Lésions non cibles
Nouvelles lésions
Réponse
  30% de la taille des lésions cibles
Stabilité
Progression
  20% de la taille des lésions cibles
OU  des lésions non cibles
OU nouvelle lésion

9. +20% -30% % variation of the sum Progressive disease PD
Stable Disease SD
Partial Response PR
-30%
Treatment
cycles
BASELINE 1 2 3 4 5

10. +20% +20% -30% % variation of the sum Progressive disease PD
Time to progression
Treatment
cycles 1 2 3 4 5

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

12. Functional evaluation
DCE-Imaging
Functional evaluation

13. precontrast
90 s
postcontrast

14. Regions of interest (ROIs) over time1 2 3 4 1 2 3 4

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

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

22. Modélisation Analyse compartimentale Interstitium q inter 3 Artere
k(3,2)
k(2,3)
k(2,1)
Artere
q artere 1
Capillaire
Q cap 2
A l’inverse des déscriptions “simplifiées” phénoménologiques,
Les modélisations mathématiques permettent d’obtenir des paramètres quantitatifs “reproductibles” et comparables
MAIS nécessite des données de grande qualité, des logiciels de traitement … pas encore standardisé
k(0,2)
q Tumeur

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)
-22.9
[-27.3; -5.7
-6.1
[-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)
-29.2
[-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)
-22.9
[-27.3; -5.7
-6.1
[-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)
-29.2
[-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
01/12/04
BF : 130
Patient porteur de métastase surrénalienne de K du rein.
Bon répondeur sous SUTENT. Chute de la perfusion (BF) SANS modification de taille
16/06/05
BF : 18

27. RCC metastasis under anti-angiogenic therapy: Poor responder
03/01/05
BF : 250
Patient porteur de métastase surrénalienne de K du rein.
NON répondeur sous SUTENT. Pas de modification de de la perfusion (BF) ni modification de taille
12/04/05
BF : 230

28. DCE-CT vs morphology Blood Flow maps Size variation (%) Baseline
Cycle 1 – 6 weeks
Cycle 4 – 30 weeks
05/05 1 2 3 4 5
-40
-35
-30
-25
-20
-15
-10 -5
Size variation (%)
Patient porteur de métastase de K du rein.
Rapidement bon répondeur sous SUTENT. Chute de la perfusion PUIS échappement avec ré-ascenssion de la perfusion avec de minimes modificatin modification de taille (qui sont retardées).

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)
245.3
[130.3; 453.5]
119.5
[74.1; 224.3]
190.5
[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]
[8.7; 9.3]
0.12
Sum of longest diameters
(mm)
104.0
[76.0 ; 252.0]
155.0
[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 #2

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

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;10:46-58
57% des K % des K % des K
5% des L.Bénignes % des LB % des LB
Kuhl Eur. Radiol.2000;10:46-58

42. Remarques techniques

43. Correction des mouvements respiratoires

44. Arterial input function
• True individual AIF
• Mean AIF
• Synthetic AIF 44

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

46. Tumor treatment
Tumor volume
Hours/Days
function
Weeks