DCE-US

Réponse tumorale : quel niveau de
validation pour de nouveaux critères ?
Nathalie Lassau MD PhD
Gustave-Roussy. Villejuif.
IR4M. UMR 8081. Université Paris Sud .France
Nouveaux traitements ciblés en cancérologie ++++
 Destruction de néovascularisation avec apparition nécrose
Souvent sans modification du volume tumoral
Critères OMS ou RECIST inadaptés (OMS: a x b, RECIST: c)
Schwarz RSNA 2005, Benjamin ASCO 2006 …..
 Imagerie fonctionnelle avec quantification
Plus de 500 molécules en pré-clinique et 80 en recherche clinique
axb
vant traitement
c
En cours de traitement Après traitement

Personalized Cancer Medecine
Kerr Nature Review 2011
Padhani Eur J Nucl Med Mol Imag 2010
Lassau Future Oncology 2012
O’Connor et al . Nature Reviews. Clinical Oncology 20122012
 Predictive biomarkers: predicts the effect of treatment
 Prognostic biomarkers: not related to the effect of treatment
 Level of validation (Oxford) :
 Pre-clinical studies
 Clinical mono-centric study
 Multi-centric study +++ with correlation with PFS and OS +++
 DCE-MRI or DCE-US : no data for multi-centric study in DCE-MRI…
 DCE-MRI : 100 mono-centric studies, > 1000 patients
 DCE-US : 8 mono-centric studies and 1 multi-centric / 700 patients
Imagerie Fonctionnelle :paramètres d’intérêts
Pas de consensus :
paramètres, timing, quel cut-off?
:
- flux sanguin tissulaire :
BF= F/Vt
- volume sanguin tissulaire : BV= Volume des capillaires /Vt
- temps de transit moyen :
MTT = BV/BF
(temps moyen mis par une particule pour traverser le tissu)
- perméabilité capillaire: Kps: fuite à travers l’endothélium
- Volume de distribution interstitielle : Vi
artère
veine
flux F
Volume V de tissus
Guide d’interprétation en
imagerie fonctionnelle. De
Bazelaire et al. JFR 2006.
N°66
1 cible
Résolution temporelle
DCE-US : 4 per sec +++
DCE-MRI : 1 every 2 sec
CT perfusion : 1 per seconde
Standardiser les temps d’acquisitions….
Metastase de cancer du colon : wash-out avant 30 secondes ….
Corrélation

on mesure :
- le BV : aire sous la courbe AUC ~ BV
max de rehaussement max ~ BV
- le BF :
pente max de rehaussement ~ BF
- le MTT : largeur à mi-hauteur de la courbe
Ct(t)
max
pente max
temps
 Bibliographie Imagerie fonctionnelle : IRM,
CT, US, Pet-scan
 Gwyther. Annals of Oncology 2005
 Schnall et al. JCO 2006
 Atri. JCO 2006
 Barentsz et al. JCO 2006
IRM
Relation non-linéaire entre l’intensité du signal et la
concentration de l’agent de contraste doit être absolument prise
en compte. Heilmann, Kiessling et al. Invest Radiol 2006.
 Phase I Molecular and Biological Evaluation of
rhuMAb-VEGF Antibody
A Determination of tumor endothelial
permeability after 2 days (MRI).
A metastasis (yellow arrow) in the
liver before therapy.
B After treatment : major effect was seen
when the dose was at least 1 mg/kg.
100
0.3 mg/kg
80
% maximum
permeability
60
1-10 mg/kg
40
20
0
Day 0
Jayson GC et al. J Natl Cancer Inst 2002; 94: 1484-1494.
Day 2
Day 35
 Fusion d’image : K trans d’une méta hépatique
avant Tt, J2, J 28 sous Tt anti-angiogénique
 Drevs et al. J Internal Medecine 2006
Métastase pulmonaire de
RCC par DCE-MRI:
Area under the curve
(AUC) avant et 2 j
Liu et al. JCO 2005
Phase I : AG-013736
Corrélation AUC et K trans
Tumeur : carcinome
adénoide kystique
DCE-MRI (Jayson et al. )
A lot of heterogenous results since 2002
December 2012
39 RCC treated with sunitinib
 Evaluation with Choi criteria at 2 months
Correlation with PFS
p=0.0043
M.-R. El Bejjani, L Rocher MF Bellin, N Lassau . ECR 2014
RCC treated with Sunitinib
PFS = 10 months
Lymphadenopathy at
baseline
Lymphadenopathy at 2
months
45mm, 104 HU
41mm, 30 HU
Uniquement
changement du
cut-off de la somme
des diametres
Analyse multicentrique
retrospective :
Patients traités par
everolimus
Cut- off :
30 % RECIST
Versus
Cut-off : 5 %
Oudard et al. 2012

DCE-CT for monitoring response in a patient with metastatic clear cell renal cell
carcinoma to the left adrenal gland.
Color perfusion CT maps a before and b one cycle : decreased blood volume
Evaluation of Treatment Response in Patients with Metastatic Renal Cell Carcinoma:
Role of State-of-the-Art Cross-Sectional Imaging
V Katabathina, N Lassau, I Pedrosa, S Prasad. Curr Urol Rep 2011
 CT-Perfusion
Fournier, Cuenod et al. Radiology 2010




Sorafenib: 9 pts
Sutent : 17
Placebo : 13
Interféron : 5
 CT-perfusion avant Tt et à 1 cycle (4 à 6 semaines )
 Flux sanguin, Volume sanguin tissulaire, Coeff de
perméabilité
 Avant Tt et après 1 cycle
Avant Tt
Flux
Vol. Vasc
BR
245
15,5
MR
119
8,2
BR
Flux
Vol. Vasc
K trans
Avt Tt
162
9
9,1
À 1 cycle
67
3,9
4,1
Scanner Perfusion
Flux sanguin
Pr CA Cuenod. Dr L Fournier JFR 2007
Métastase de cancer du rein sous Sutent
Répondeur
01/12/04
BF : 130
16/06/05
BF : 18
Non répondeur
03/01/05
BF : 250
12/04/05
BF : 230
HCC treated with TKI
2 modalities: CT-perfusion and
DCE-US
Only DCE-US at 1 month
(decrease < 40 %) was correlated
to response
 Ou en est-on de la validation de la DCE-MRI ?
 Liver metastasis of colon cancer
treated with Bevacizumab
Monocentric studies, small population
Very often K Trans
 Recommendations :





Tofts model with arterial input
acquisitions > 8-10 mn
Lesion > 3 cm
2 baselines
K Trans
n
27 patients with Metastatic Colon Cancer :
chemo+ bevacizumab
Pet-CT Evaluation after 3 weeks
 Correlation PET-CT with PFS and not OS
 Et la DCE-US ?
 Quel niveau de validation ?

Work in progress Automatic tracking takes few secondes
Courtesy Pr Moriyasu. Tokyo University
- Bolus injection
- 3 mn of acquisition  AUC
- Raw linear data
6 monocentric Studies: Correlation DCE-US and Response
HCC
Avastin**
RCC
Sutent*
GIST
Masatinib
***
Phase I:
Nexavar ****
HCC
Sutent/
Nexavar *****
HCC/
Nexavar
******
patients = 164
42
38
20
17
19
28
DCE-US> 900
263
168
263
117
38
84
AUC
0.03
0.008
0.004
0.04
0. 01
0.002
AUC Wash-in
0.03
NS
0.002
0.01
ND
ND
AUC Wash-out
0.02
0.01
0.002
0.04
ND
ND
slope
NS
0.0005
0.003
NS
ND
0.003
Peak intensity
NS
0.002
0.005
0.02
ND
0.001
TTP
NS
0.007
NS
NS
ND
NS
MTT
NS
NS
NS
NS
ND
NS
Parameters
Clin Cancer Research 2010*, Radiology 2011**,
Invest New Drugs 2012*** Invest New Drugs 2013 ****, Eur Radiol 2013 *****,
J Hepatol 2013******
 RCC and Sunitinib
DCE-US after 15 days
Contrast uptake curves
350
300
Intensity
250
200
150
100
50
0
0.00
20.00
40.00
13/11/2006
60.00
27/11/2006
80.00
100.00
12/3/2007
120.00
2/7/2007
140.00
6/8/2007
160.00
Blue: before tratment Pink : D 15 Yellow : C4
Turquoise : C6 purple: C8
CT at 3 months
180.00
200.00
Time (sec)
 French National Program of DCE-US from 2007-2009 :
STIC
910 000 euros from the Ministry of Health (INCA)
250 000 euros from Toshiba and 350 000 euros from Bracco
 To extend and validate our methodology using raw linear data
 To demonstrate the feasibility of DCE-US in 19 hospitals.
 To determine :
• which is the best parameter,
• which cut-off ?
• which timing is decisive for evaluating response to
antiangiogenic therapies ?
 To assess the economic impact of DCE-US : Prospective Cost
study.
 Methodology: Standardization
5
Quantification
600
donnees brutes
modele
500
1
2
3
400
300
Toshiba
Aplio or AplioXG
Selection
of 1 target
2 Probes
Abdo (PVT 375 BT)
Superf (PLT 805 AT)
Bolus
Injection
Sonovue®
4.8 ml
2 Settings
Abdo or Superf
Workflow
IAssist
4
Raw data
acquisition
3 min
Examination by Radiologist
200
100
0
0
6
20
40
60
80
100
120
140
-100
Modelization
IGR Patent
• Peak intensity
• Time to peak
• Slope
• Mean transit time
• Area under the curve
• Area under the wash-in
• Area under the wash-out
7
Parameter
evaluation
Image analysis
 539 patients
 The median follow-up : 20 months +++
 2055 DCE-US
 1734 CT-scans
 Histological type : number of patients
 RCC : 157
 HCC : 107
 Colon cancer : 67
 Breast : 61
 Melanoma : 52
 GIST : 52
 others : 43
 Localisation of target lesions
 Liver lesions (55%)
 Others lesions: lymph node , peritoneal, pelvic (45%)
Nom bre de patients inclus
 Final inclusion March 2010
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8
20 08
s em 25 /0
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s em 21 /0 6/2 008
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/2 0 9
s em 20 /0 3
9
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0
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14 8/2 009
s
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1/2 009
10
 Population
600
500
400
300
200
100
0
Semaines
• Main treatments
• Sorafenib : 166
• Bevacizumab : 144
• Sunitinib: 128
• Imatinib : 44
• Other/combinations: 57
Distribution of quality scores : 97 % > quality 0
The quality score depends:
lesion size,
target motion,
loss of target,
clear borders,
total acquisition of wash-in,
VRI window adapted to the lesion size.
 Statistical significance of the correlations
between DCE-US parameters and TTP at 12 months
Significant
Pvalues
Baseline
Day 7
Day 15
D 30
Peak
intensity
0.006
Slope
0.004
MTT
0.002
Variat PI
0.00003
Variat
AUWI
0.00003
Variat
AUWO
0.00002
Variat
AUC
0.00002
These P-values are significant even if we apply a Bonferoni correction to take into account multiple testing
Time to progression in the 2 classes defined by the cut-point
selected for the variation of Area under the Curve
Decrease of AUC > 40 % at 1 month
Overall survival in the 2 classes defined by the cut-point
selected for the variation of Area under the Curve
New Chapter 22: Tumour Response Assessment
Recommended uses and indications :
DCE-US can be utilised to assess response to biologic therapy in metastatic GIST
and other metastatic tumours, e. g. renal cell carcinoma, in dedicated centres with
appropriate software for contrast signal quantification.
Evidence Based medicine (Oxford)
Recommendation Level: A;1b ++++
 Conclusion :
 DCE-US : validation avec étude multi-centrique (> 500 patients)
• Diminution > 40 % de AUC à 1 mois
• Corrélation avec PFS et OS
• Manque étude clinique de variabilité : en cours ….
 Scanner :
 Critères Choi pour GIST, RCC et HCC ? :
• robuste et facile d’utilisation
 CT-perfusion : pas de validation en multi-centrique
 DCE-MRI : un nombre important d’études mono-centriques
 Validation en multi-centrique avec le STIC CA Cuenod et L Fournier
 Pet-CT : critères EORTC en mono-centrique
 valider en multi-centrique