Clinical Imaging Hypoxia
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Transcript of Clinical Imaging Hypoxia
Imaging of hypoxia
Philippe Lambin
Octobre 12th 2012
This course is funded with the support of the METOXIA project under the FP7 Programme.
Learning objectives
1. Know the advantages and disadvantages of hypoxia imaging
2. Be able to name the various hypoxia imaging modalities with some basic features
Advantage of imaging: 3D & non invasive
Advantageous compared to IHC, gene-miRNA signatures because tumours are heterogeneous in space
Courtesy of B. van der Kogel
4
Disadvantage: The oxygen distribution inside a voxel
Measured voxel pO2 is average pO2 of the cells inside it.
Each voxel contains a mixture of cells at different oxygen concentrations.
Ignoring this will affect the correct choice of dose.
Why should we do it?
For prognosis (Give prognosis of disease outcome regardless of therapy)
For prediction (Predict outcome with a specific therapy & allow to adapt treatment (drugs, boost BTV…)
As endpoint (secondary or primary: e.g. reduction of hypoxia with nitroglycerine patch, pattern of relapse…)
For research purposes (no immediate clinical benefit)
How to measure tumor oxygenation ?
Non Imaging methods
• Polarographic measurements• Eppendorf®
• Optical measurements• Phosphorescence• Fluorescence (OxyLite ®)
• Hypoxia markers• Nitroimidazoles
• Immunohistochemistry
• Gene signatures
• Blood biomarkers
Imaging methods
• Hypoxia markers• Nitroimidazoles PET/SPECT• CA9 ligands PET/SPECT
• MR• 19F relaxation• BOLD• DCE-MRI• 1H relaxation
• EPR-related methods
B. Gallez, NMR Biomed. 2004, 17, 240
How to measure tumor oxygenation ?
Real oxygenmeasurements
• Polarographic measurements• Eppendorf®
• Optical measurements• Fluorescence (OxyLite ®)
• EPR-related methods
• MRI• 19F relaxation
Oxygen-sensitivemeasurements
• NMR• DCE-MRI• BOLD• 1H relaxation
• Hypoxia markers• Nitroimidazoles
• Immunohistochemistry• PET/SPECT
• CA9 ligands PET/SPECT
• Gene signatures
• Blood biomarkers
How to measure tumor oxygenation ?
InvasiveOr not immediately
clinically applicable
• Polarographic measurements• Eppendorf®
• Optical measurements• Fluorescence (OxyLite ®)
• EPR-related methods
• MRI• 19F relaxation
ImagingClinically applicable
• NMR• DCE-MRI• BOLD• 1H relaxation
• Hypoxia markers• Nitroimidazoles PET/SPECT• CA9 ligands PET/SPECT
Used to qualify
the clinically applicable
oxygen-sensitive
techniques
Real oxygen
measurements
Ideal clinical oxygen imaging modality
• Able to distinguish normoxia/hypoxia/anoxia/necrosis
• Able to distinguish between perfusion-related and diffusion-related hypoxia (sensitive to changes of hypoxia)
• Able to reflect cellular oxygenation in preference to vascular oxygenation
• Be applicable to any tumor site
• Simple to perform, non toxic and allowing repeated measurements
• Sensitive at pO2 relevant to tumor therapies
• Results independant of the timing of imagingA. Padhani, Eur. Radiol. 2007, 17, 861.
EPR (Electron Paramagnetic Resonance) Oximetry
O2 dependent broadening of the EPR
linewidth (LW) of a paramagnetic O2
sensor implanted in the tumor
A particular material can be calibrated in terms of the effect of oxygen on the LW
When introduced in vivo, the measurement of LW can be interpreted in terms of oxygenation in the vicinity of the probe
3168 3318 3468
Magnetic Field (G)
0
10
20
30
40
0 7 14 21
% O2
LW
(G
)
air
nitrogen
B. Gallez, NMR Biomed. 2004,17, 240
Non-invasive imaging of chronic and cycling tumour hypoxia in xenografts with
EPR
Yasui et al., 2010, Can Res, 70:6427-6436.
EPR (Electron Paramagnetic Resonance) Oximetry
• Absolute measurement of pO2
• High sensitivity at low pO2: variations
lower than 1 mm Hg can be measured
• Minimally invasive: few microparticles should be introduced in the tissue (invasive only the first time)
• Measurements can be repeated from the same site over long periods of time (hours, days, months)
• 1GHz: penetration depth of 1 cm
• Not applicable immediately into the clinic: pionneer clinical studies ongoing in Dartmouth Medical School on superficial tumors
N. Khan, Antiox. Redox. Signal. 2007, 9, 1169
19F-relaxometry
Mason RP et al, IJROBP 1998, 42, 747; and following works of Mason’s group
• Intratumoral injection of PFC (i.e. hexafluorobenzene, single 19F line)• Measurement of the R1 relaxation of 19F relaxation that is strongly dependent on pO2
• Maps of pO2
19F-relaxometry
Rapid estimation of R1 using SNAP-IR sequence
Simultaneous monitoring using 19F-MRI and fiber optic probes
B. JordanMRM 2009, 61, 634-638
19F-relaxometry
Problem to inject the PFC in the
entire tumor
The technique is likely to slightly overestimate pO2
Not applicable for chronic purposes (only acute studies)
Toxicity concerns with some PFCs
Lack of translation into the clinic (invasiveness, 19F coils)
Rather sensitive method
Quantitative method: pO2
values
No 19F NMR background signal in tissues
Good temporal & spatial resolutions for O2 mapping
DCE-MRI
Attempt to correlate DCE-MRI parameters with tumor hypoxia
(Gribbestad., Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Oncology, 2006)
Ktrans significantly higher for radiation sensitive tumors
without hypoxia than for radiation resistant
tumors with hypoxic regions
K Gullisksrud, Radiother. Oncol. 2011, 98, 360
Dynamic MRI of cervix carcinoma
C DModified from:J. Barentsz
A. T2-weighted spin echo imageB. [Gd] max imageC. [Gd] time-to-peak image
3
2
a
4
1A B
C Dt
[Gd] 123
4
a
Tumor Oxygenation
Perfusion Oxygen consumption
High O2 consumption rate by tumor cells
Cancer cells consume oxygen at high rate, even if they generally present a highly glycolytic metabolism
This high consumption rate significantly contributes to the tumor hypoxia resulting from the imbalance between oxygen delivery and oxygen consumption
Strategies to decrease the oxygen consumption by tumor cells and potentiate radiotherapy
• Meta-iodobenzylguanidine JE Biaglow, IJROBP 1998, 42, 871
• Nitric oxide donors B. Jordan, Int. J. Cancer 2004, 109, 768
• Insulin B. Jordan, Cancer Res. 2002, 62, 3555
• NSAIDs N. Crokart, Cancer Res. 2005, 65, 7911
• Glucocorticoids N. Crokart, Clin. Cancer Res. 2007, 13, 630
• SU5416, ZD6474 R. Ansiaux, Cancer Res. 2006, 66, 9698; Radiat. Res. 2009, 172, 584
• Propylthiouracil B. Jordan, Radiat. Res. 2007, 168, 428
• Arsenic trioxide C. Diepart, submitted
Theoretical simulations:
To alleviate tumor hypoxia, decreasing the O2 consumption rate of tumor is more effective than increasing
oxygen deliverySecomb, Acta Oncol. 1995 34, 313
Pre-clinical studies
DCE-MRI
Trend of perfusion
parameters to differentiate between hypoxic vs normoxic tumors
Clinically usable
No absolute values of pO2
It is unlikely that a treshold value of a DCE-MRI parameter will predict the radiosensitivity
Tumor perfusion is not the main or sole factor that is responsible for the tumor oxygenation (oxygen consumption)
BOLD-MRI – R2*
Oxy-Hemoglobin: diamagneticDeoxy-Hemoglobin: Paramagnetic
S. Ogawa et al, PNAS 1990, 87, 9868
Carbogenbreathing
From fMRI …… to tumor oxygenation
GS Karczmar, NMR Biomed 1994, 12, 881SP Robinson, IJROBP 1995, 33, 855F Howe, MRI 1999, 17, 1307
Level of blood oxygenation DeoxyHb /OxyHb blood content SI
BOLD-MRI
T2* is sensitive to the relative Hb/HbO2 ratio in vessels:
Blood oxygen saturationHematocrit
Blood volume
Basal R2* and tumor oxygenation
Correlation between pimonidazole uptakeand high R2* in prostate cancer
PJ Hoskin, IJROBP 2007, 68, 1065
Inverse correlation between pimoninazoleuptake and R2* values in mammary tumors
McPhail, Radiology 2010, 254, 110
R2*: phenotype specific ?Requires simultaneous measurements of vasculature function ?
AR Padhani, Radiology 2010, 254, 1
Change in R2* and change in tumor oxygenation
T2*w SI T2*
Local
Whole tumor
pO2
BOLD signal response correctly reflected the evolution of tumor oxygenation in carbogen challenge
BOLD signal
C. Baudelet and B. GallezMagn.Reson. Med.
2002;48:980.
Comparison with OxyLite: simultaneous measurement of R2* and pO2
Tumor Oxygenation
Perfusion Oxygen consumption
Change in R2* and change in tumor oxygenation
Increase in pO2 through changes in O2 consumption
Insulin infusion Control NS-398
Changes in BOLD signal and R2* in tumors do not depend uniquely on changes in oxygenation status
B. Jordan, MRM 2006, 56, 637
BOLD-MRI and R2*
Variations in tumor oxygenation
can be qualitatively measured during carbogen breathing
Rapid dynamic measurement
Clinically usable
No absolute values of pO2
The value of basal R2* is
debatable
Variation in R2* cannot predict
changes in oxygenation induced by treatments modulating the oxygen consumption
T1-based measurements
Carbogenbreathing
O2 O2
O2
O2 O2
O2
H20H20
H20
H20H20
O2 O2
H20 H20
H20H20
H20
Dissolved oxygen acts as a T1-shortening paramagnetic contrast agent
Oxygen produces changes in relaxation rate R1 of water
H20
H20
KI Matsumoto, MRM 2006, 56, 240
air
carb
ogen-5
0
5
10
15
20
R1 (H2O)
R1 (Lipids @ ~ 3.5 ppm)
rela
tive
ch
ang
e (%
)
0 50 100
0
10
20
30
40
50
carbogen
postmortem
air
time (min)
pO
2(m
mH
g)
Pooled resultsN=5
T1-based measurementsMOBILE
Mapping of Oxygen By Imaging Lipids Relaxation Enhancement
air carbogen postmortem
-0.4
-0.2
0.0
0.2 R1 (H2O)
R1 (Lipids @ ~ 3.5 ppm)
rela
tive
ch
ang
e (%
)
Nitro-imidazoles mechanism of uptake
• Initial distribution is flow dependent• Local oxygen tension = main determinant for long-term retention
• NO2 reduction in radical anion;
• if O2 is present, back to the original structure
• in absence of O2, second reduction with product binding to macromolecules
• depends on the nitroreductase activity• generally assumed to have retention under 10 mm Hg
RNO2 RNO2
necrosisRNO2
-e- reduction
normoxia
RNH2
e- reduction
hypoxia
retentionmetabolites
vascular space cellular compartment
Nitroimidazole-based PET: How does it work?
Rat rhabdomyosarcoma: optimizing imaging conditions with HX4
0 1 2 3 4 5 6
0
2
4
6
8
Time (hours) after injection
max
Tiss
ue to
Blo
od ra
tio
*
**
*
NS NS
4h p.i.
Dubois et al. PNAS 2011
Is there a significant correlation between pimonidazole staining (“the gold standard”) and HX4 uptake?
Validation of 18F-HX4 uptake using IHC (setup)
region selection based on CT %HX4 per region
DORSAL
HEAD
TAIL
VENTRAL
a b c d
ab
cd
Dubois et al. PNAS 2011
Validation with pimonidazole IHC: first results
Courtesy of B. van der KogelDubois et al. PNAS 2011
Validation of 18F-HX4 uptake using IHC (results)
n = 76
0.07330.6627III-3
0.00020.8202II-3
< 0.00010.9046I-2
0.00550.6588III-2
0.00280.7334III-1
< 0.00010.7222regions
0.28480.6000total
p-valueSpearman R
%PIMO vs %HX4 summary
Dubois et al. PNAS 2011
Is there a causal relationship between hypoxia and HX4 uptake?
[18F]HX4 accumulation is oxygen dependent
Basal scan Carbogen/Nicotinamide
7% oxygen breathingBasal scanDubois et al. PNAS 2011
Which hypoxic biomarker is the best?
Hypoxia PET tracers
18F-FMISO 18F-FAZA 18F-HX4
Nitro-imidazoles:
• Clearance:
• Hydrophilicity:
Liver –intestine – kidney
Kidney – intestine – liver
Kidney – bladder
Positron-emitting
radionuclide
Hypoxia sensitive
partRest group
Tumor to blood
S. Peeters et al. In preparation
Imaging HypoxiaPrognostic value of outcome
F-MISO PET in 73 patientswith H&N cancer
FMISO Tumor/Bloodis a prognostic measure
of the outcome
JG Rajendran, Clin. Cancer Res. 2006, 12, 5435
Correlation also found in:
FMISO PET in 40 patients with H&N cancerSM Eschmann, J. Nucl. Med. 2005, 46, 253
No correlation found in:
FMISO PET in 20 patients with H&N cancerNL Lee, IJROBP 2009, 75, 201
Copyright © American Society of Clinical Oncology
Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006
(A) Baseline [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of patient with T2N2b squamous cell carcinoma of the pyriform fossa with left nodal mass
(A) Baseline [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) of patient with T2N2b squamous cell carcinoma of the pyriform fossa with left nodal mass.
(B) (B) [18F]-fluoromisonidazole (FMISO) -PET at baseline, nonhypoxic primary tumor, and hypoxic node.
(C) C) FDG-PET 12 weeks after chemoboost, complete response in nonhypoxic primary tumor, and poor response in hypoxic node. Residual tumor in nodal mass was confirmed pathologically after neck
dissection.
Phase 1 HX4 imaging: clinically feasible?Van Loon et al, EJNM 2010
CT delineated tumor [18F]HX4 accumulation
0
0,4
0,8
1,2
1,6
30 60 120
Time (min) after injection
T/M
Van Loon J. et al. EJNM 2010
NSCLC Stage IIIB
18HX4-PETCT
Van Loon et al. Eur J Nucl Med Mol Imaging. 2010
Copyright © American Society of Clinical Oncology
Rischin, D. et al. J Clin Oncol; 24:2098-2104 2006
Time to local failure (Kaplan-Meier method) by treatment arm and hypoxia in the primary tumor (censored times are indicated as tick marks on the curves)
Zips et al. Radiother Oncol 2012
Zips et al. Radiother Oncol 2012
Zips et al[18F]Misnidazole
0 Gy 10 Gy 20 Gy 40 Gy
[18F]Misonidazol
[18F]FDG
Zips , Kotzerke, Baumann et al.
Biomarker: Hypoxia (F-MISO PET)
Department of Radiation Oncology M. Baumann |Regaud Lecture 2012
Radiolabelled nitroimidazoles
Hypoxia-sensitive method
Relevant to estimate radioresistant relevant hypoxia (< 10 mm Hg)
Clinically usable
Prognostic value (especially if repeated)
No absolute values of pO2
Poor correlation with pO2 values
for some tracers
Accumulation dependent on the level of nitroreductases
Imaging of tumor acute hypoxiaSpontaneous fluctuations in tumor oxygenation/perfusion
Technique Spatial resolution
Temporal resolution
Characteristics Reference
NITRO-PET 4.2 mm Day 1,2,5 Hypoxia (More or less
than 10 mm Hg)
Wang,Med. Phys.
2009, 36, 4400
DCE-MRI 0.5x0.2 mm3 15 min Flow variation Brurberg,MRM
2007, 58, 473
T2*w-GE MRI 470x470 µm2 12.8s Oxygen/flow variation
Baudelet, Phys. Med. Biol. 2004, 49, 3389
19F-MRI 1.88 mm 1.5 min Quantitative pO2
Magat,Med. Phys.
2010, 37, 5434
EPRI 1.8 mm 3 min Quantitative pO2
Yasui,Cancer Res.
2010, 70, 6427
*P < 0.05; **P < 0.01
In vivo CAIX specific sulfonamide accumulation is reversible upon reoxygenation
Dubois et al, Radiother & Oncol 2009
Dubois et al, Radiother & Oncol 2009
PET images of mice with tumor located subcutaneously on right hind leg at 4 (A) and 24 h (B) after injection. p.i. = after
injection; SUV = standardized uptake value.This course is funded with the support of
the METOXIA project under the FP7 Programme.
MAb-N-succinyldesferal-89Zr (MAb-N-sucDf-89Zr) (*)
Imaging of CAIX with antibody
Hoeben, Kaanders et al. 2010 Jul;51(7):1076-83.
How to include hypoxia imaging in the clinic?
Exploiting intra patient heterogeneity for dose painting of radiation
Intensity modulated radiation therapy (IMRT)
Possibility to sculpt the doses as a function of possible needs
Galvin, J. Clin. Oncol. 2007, 25, 924
Hypoxia Guided IMRT: dose escalation in hypoxic areas
Dose Painting by Contours
Dose Painting by Numbers
0.4
0.6
1.1
1.9
2.7
2.9
Proof-of-concept using Cu-ASTM
KSC Chao, IJROBP 2001, 49, 1171
Theoretical feasibilityusing 18F-FMISO
Dose prescription based on tumor hypoxia
D. Thorwarth, IJROBP 2007, 68, 291Z. Lin, IJROBP 2008, 70, 1219NY Lee, IJROBP 2008, 70, 2
I. Toma-Dasu, Acta Oncol. 2009, 48, 1181W. Choi, Radiother. Oncol. 2010, 97, 176
Hypoxia Guided IMRT: dose escalation in hypoxic areas
Dose Painting by Contours
Dose Painting by Numbers
0.4
0.6
1.1
1.9
2.7
2.9
Proof-of-concept using Cu-ASTM
KSC Chao, IJROBP 2001, 49, 1171
Theoretical feasibilityusing 18F-FMISO
Dose prescription based on tumor hypoxia
D. Thorwarth, IJROBP 2007, 68, 291Z. Lin, IJROBP 2008, 70, 1219NY Lee, IJROBP 2008, 70, 2
I. Toma-Dasu, Acta Oncol. 2009, 48, 1181W. Choi, Radiother. Oncol. 2010, 97, 176
Conclusions
• To bridge the gap between hypoxia-induced radioresistance and optimized radiotherapeutic treatment with drugs
– Oxygenation imaging is mandatory
– Qualification of oxygenation biomarkers is still mandatory at the pre-clinical and the clinical level
– There is a crucial need to validate the value of hypoxia-gimaging inprospective trials with interventions
ISMRM 2011: Clinical Needs and Research Promises
AcknowledgementsUniversity of Nijmegen (The Netherlands)
– Albert van der Kogel– Jan Bussink– Hans Kaanders
University of Amsterdam (VUmc)– Guus van Dongen– Bert Windhorts– Jonas Eriksson
University of Florence (Italy)– Andrea Scozzafava– Claudiu Supuran
University of Brussels (UCL)– Bernard Gallez*– Vincent Grégoire
Our patients (No immediate benefit for them)
Euroxy-Metoxia 6th & 7th Framework
NIH (USA)
Siemens MI
University of Maastricht– Ludwig Dubois *– Judith van Loon – Sarah Peeters – Karen Zeghers