Transcript Dynamic CT imaging (DCE-CT) in the anti-angiogenic response

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
Tumour angiogenesis is a
major topic in oncology
1971 Judah Folkman
New England Journal of Medecine
Tumour neo-angiogenesis
« Under the stimuli of malignant cells, the
endothelial cells build a complete new
network of capillaries »
R Jain
Tumor angiogenesis
IGF-1
PDGF
EGF
IL-8
Growth Factors
H2 O 2
VEGF release
bFGF
Binding and activation
of VEGF receptor
Hypoxia 
COX-2 
NO 
Oncogenes 
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
P–
P–
Survival
–P
–P
Proliferation
Angiogenesis
Migration
Permeability
Folkman. NEJM 1971;285:1182-1186
Avastin
Sorafenib / Nexavar
Endothelial Cell membrane
Sunitinib /Sutent
Sorafenib
RAD001
Anti-angiogenic
treatment
Patel Br J Cancer 2006
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
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
% variation of the
sum
Progressive disease PD
+20%
Stable Disease SD
-30%
Partial Response PR
0
BASELINE
1
2
3
4
5
Treatment
cycles
% variation of the sum
Progressive disease PD
+20%
+20%
-30%
Time to progression
1
2
3
4
5
Treatment
cycles
Size variation in RCC
under anti-angiogenic treatment vs. placebo
Groupe placebo
Placebo
Groupe
sous traitement
Treatment
DCE-Imaging
Functional evaluation
precontrast
postcontrast
Regions of interest (ROIs) over time
4
1
2
1
4
3
2 3
Patients
 Patients:
Metastatic RCC
 April 2004-May 2006
 Clinical trials:
Sorafenib / Nexavar® vs. placebo
Sunitinib / Sutent® vs. interferon
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
Choice of functional target
 Size > 2 cm
 Minimal movements
Retroperitoneum > mediastinum > lung
 Not liver or bone (medullary)
Results
ARTERY (Arterial Input Function)
Tissue response
Main microvascular parameters
Fractional intersitial volume
Regional
blood
perfusion
(%)
(ml/min/100ml)
Fractional
Blood
volume
(%)
OUT
IN
Permeability
x surface
(ml/min/100ml)
Main microvascular parameters
Ve (%)
FT
(ml/min/100ml)
BV
(%)
OUT
IN
PS
Mean Transit time
(ml/min/100ml)
TTM= VB/FT
Dependent on tracer
Modélisation Analyse compartimentale
Artere
q artere
k(2,1)
k(2,3)
Capillaire
Q cap
1
2
k(0,2)
Interstitium
q inter
k(3,2)
q Tumeur
3
Can we detect an effect on tumour vessels
after a single cycle of treatment by antiangiogenic drugs?
Placebo
N=8
Interferon
N=5
Tissue Blood flow
(ml/min/100ml)
-22.9
[-27.3; -5.7
-6.1
[-18.8; 0.8]
Antiangiogenic
N=25
-50
[-72;-3]
Tissue Blood volume
(%)
Mean transit time
(s)
-4.2
[-22.0; 5.6]
17.0
[7.4; 28.5]
2.0
[-5.5; 18.0]
-2.4
[-10.2; 16.6]
-51
[-67;-24]
5
[-22;73]
-29.2
[-47.4;-14.5]
16.4
[-11.9;20.9]
-34*
[-83 ; 8]
5.5
[-1.0; 11.8]
-3.8
[-16.5; -0.7]
-17
[-29.0; -7.0]
Variable* (%)
Permeability surface
area product
(mL/min/100ml)
Sum of longest
diameters (mm)
* Significant for Nexavar, not Sutent
Placebo
N=8
Interferon
N=5
Blood flow
(ml/min/100ml)
-22.9
[-27.3; -5.7
-6.1
[-18.8; 0.8]
Antiangiogenic
N=25
-50
[-72;-3]
Blood volume
(%)
Mean transit time
(s)
-4.2
[-22.0; 5.6]
17.0
[7.4; 28.5]
2.0
[-5.5; 18.0]
-2.4
[-10.2; 16.6]
-51
[-67;-24]
5
[-22;73]
-29.2
[-47.4;-14.5]
16.4
[-11.9;20.9]
-34
[-83 ; 8]
5.5
[-1.0; 11.8]
-3.8
[-16.5; -0.7]
-17
[-29.0; -7.0]
Variable* (%)
Permeability surface
area product
(mL/min/100ml)
Sum of longest
diameters (mm)
RCC metastasis under anti-angiogenic therapy:
Good responder
01/12/04
BF : 130
16/06/05
BF : 18
RCC metastasis under anti-angiogenic therapy:
Poor responder
03/01/05
BF : 250
12/04/05
BF : 230
DCE-CT vs morphology
Baseline
Blood Flow maps
Cycle 1 – 6 weeks
Cycle 4 – 30 weeks
0
-5
Size variation (%)
-10
-15
-20
-25
-30
-35
-40
05/05
1
2
3
4
5
Can baseline parameters as measured by
functional imaging predict future tumour
response?
Stable
N=20
Progression
N=2
P (S vs. R)
119.5
[74.1; 224.3]
190.5
[162.5; 218.5]
0.04
15.5
[9.0; 24.5]
8.2
[5.6; 14.9]
9.6
[9.2; 10.1]
0.02
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)
104.0
[76.0 ; 252.0]
155.0
[91.0 ; 198.5]
73.0
[50.0 ; 96.0]
0.18
Variable (%)
Response
N=10
Blood flow
245.3
(mL/min/100ml) [130.3; 453.5]
Blood volume
(mL/min/100ml)
Mean transit
time (s)
Limits – clinical study
 Difficulties
50% of patient data incomplete or
data analysis failed
102 patients in clinical trial
51 patients successful DCE-CT
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%)
AIF
Limits – clinical study
 Inter-investigator reproducibility
2 investigators
Blood flow – investigator #2
800
Flux sanguin M2 (ml/min/100gr de tissu)
700
R r=0.91
=S***0.91
R²R2=0.82
= 0.82
600
500
400
300
200
100
0
0
100
200
300
400
500
600
700
800
Flux sanguin M1 (ml/min/100gr de tissu)
Blood flow – investigator #1
PS – investigator #2
65
60
Perméabilité M2 (ml/min/100gr de tissu)
55
50
R r=0.45
= **0.45
S
2
R²R==0.2
0.20
45
40
35
30
25
20
15
10
5
0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
27.5
Perméabilité M1 (ml/min/100gr de tissu)
PS – investigator #1
30.0
Clinical study: conclusions
DCE-CT can be used in a clinical context
Difficulties to implement the technique
• organisation +++
• motion (lung metastases)
IRM vs CT
Profil «
Critères
dynamiques
malignité » ….. « bénignité »
Kuhl Eur. Radiol.2000;10:46-58
57% des K
5% des L.Bénignes
34 % des K
12% des LB
Kuhl Eur. Radiol.2000;10:46-58
9% des K
83% des LB
Remarques techniques
Correction des mouvements respiratoires
Arterial input
function
• True individual AIF
• Mean AIF
• Synthetic AIF
Peak is missed
Steady state
Slope
1 image/ 10 sec
1 image / 1 min
Tumor treatment
Tumor volume
function
Hours/Days
Weeks