Dynamic CT imaging (DCE-CT) in the anti-angiogenic response in Metastatic Renal Cell Carcinoma

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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 en Imagerie, Université
  Paris R Descartes.
• Radiology, Hôpital Européen Georges Pompidou,
• Paris
• ESUR Munich 2008

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Tumour angiogenesis is a major topic in oncology

• 1971 Judah Folkman
• New England Journal of Medecine

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Tumour neo-angiogenesis

•  Under the stimuli of malignant cells, the
  endothelial cells build a complete new network of
  capillaries 

R Jain
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Tumor angiogenesis
Growth Factors
Folkman. NEJM 19712851182-1186
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Avastin
Sorafenib / Nexavar
Endothelial Cell membrane
Sunitinib /Sutent
Sorafenib
Anti-angiogenic treatment
RAD001
Patel Br J Cancer 2006
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Surrogate markers reflecting treatment efficacy
Surrogate markers reflecting treatment efficacy

• Reference tumour size
• RECIST Response Evaluation Criteria in Solid
  Tumors
• Therasse P. et al, J Natl Cancer Inst
  200092205-16
• Functional imaging measuring tumour
  vascularisation, target of anti-angiogenic drugs

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RECIST Response Evaluation Criteria in Solid
Tumors

• Therasse P. et al, J Natl Cancer Inst
  200092205-16

Measuring (and adding) the longest diameters in
targets
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Lésions cibles ? 10 mm
Lésions non cibles
Nouvelles lésions
Stabilité

• Progression
• ? ? 20 de la taille des lésions cibles
• OU ? des lésions non cibles
• OU nouvelle lésion

Réponse ? ? 30 de la taille des lésions cibles
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variation of the sum
Progressive disease PD
20
-30
Treatment cycles
0 BASELINE
1
2
3
4
5
10
variation of the sum
20
-30
Treatment cycles
1
2
3
4
5
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Size variation in RCC under anti-angiogenic
treatment vs. placebo
Groupe placebo
Placebo Treatment
Groupe sous traitement
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DCE-Imaging

• Functional evaluation

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precontrast
postcontrast
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Regions of interest (ROIs) over time
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Patients

• PatientsMetastatic RCC
• April 2004-May 2006
• Clinical trials Sorafenib / Nexavar vs.
  placebo Sunitinib / Sutent vs. interferon

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Acquisition

• 1- First exam before IV (low dose) (for target
  selection) gt 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

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Choice of functional target

• Size gt 2 cm
• Minimal movementsRetroperitoneum gt mediastinum
  gt lung
• Not liver or bone (medullary)

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Results
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Main microvascular parameters
OUT
IN
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Main microvascular parameters
Mean Transit time TTM VB/FT
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Modélisation
Analyse compartimentale
k(2,1)
Capillaire Q cap 2
Artere q artere 1
k(0,2)
q Tumeur
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• Can we detect an effect on tumour vessels after a
  single cycle of treatment by anti-angiogenic
  drugs?

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Variable () Placebo N8 Interferon N5 Anti-angiogenic N25
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 -2273
Permeability surface area product (mL/min/100ml) -29.2 -47.4-14.5 16.4 -11.920.9 -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
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Variable () Placebo N8 Interferon N5 Anti-angiogenic N25
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 -2273
Permeability surface area product (mL/min/100ml) -29.2 -47.4-14.5 16.4 -11.920.9 -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
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RCC metastasis under anti-angiogenic
therapy Good responder
01/12/04 BF 130
16/06/05 BF 18
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RCC metastasis under anti-angiogenic
therapy Poor responder
03/01/05 BF 250
12/04/05 BF 230
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DCE-CT vs morphology
Blood Flow maps
Baseline
Cycle 1 6 weeks
Cycle 4 30 weeks
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• Can baseline parameters as measured by functional
  imaging predict future tumour response?

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Variable () Response N10 Stable N20 Progression N2 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 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
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Limits clinical study

• Difficulties 50 of patient data incomplete or
  data analysis failed
• 102 patients in clinical trial51 patients
  successful DCE-CT

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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)

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AIF
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Limits clinical study

• Inter-investigator reproducibility
• 2 investigators

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Blood flow investigator 2
R 0.91 R² 0.82
Blood flow investigator 1
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PS investigator 2
R 0.45 R² 0.20
PS investigator 1
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Clinical study conclusions

• DCE-CT can be used in a clinical context
• Difficulties to implement the technique
  organisation motion (lung metastases)

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IRM vs CT
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Critères dynamiques

• Profil   malignité  ..   bénignité 

Kuhl Eur. Radiol.20001046-58
57 des K 34 des K
9 des K 5 des
L.Bénignes 12 des LB
83 des LB
Kuhl Eur. Radiol.20001046-58
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Remarques techniques
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Correction des mouvements respiratoires
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Arterial input function
True individual AIF Mean AIF Synthetic
AIF
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Peak is missed
1 image/ 10 sec
1 image / 1 min
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Tumor treatment
Tumor volume
Weeks