International Conference on Advances In Radiation Oncology ...
PET in Radiation Oncology: Advances in Chemistry,...
Transcript of PET in Radiation Oncology: Advances in Chemistry,...
8/2/2018
1
PET in Radiation Oncology:
Advances in Chemistry,
Biology, and Physics
Cancer Biology ProgramMolecular Imaging Program @ Stanford Bio-X
Stanford University School of Medicine, Department of Radiation Oncology
Edward “Ted” Graves, Ph.D. ([email protected])
Imaging in Radiation Oncology
Imaging in Radiation Oncology
8/2/2018
2
Positron Emission Tomography
• Positron emitters and radiochemistry
• Imaging technology
• Imaging targets and radiotracers
• Quantitation
Positron Emitters
Isotope Half life
(hours)
Decay Maximum
b+ energy
(keV)
Mean
b+ energy
(keV)
11C 0.34 b+ (99.8%) 960 386
13N 0.17 b+ (99.8%) 1198 492
15O 0.03 b+ (99.9%) 1732 735
18F 1.83 b+ (96.7%) 634 250
64Cu 12.70 b+ (17.4%)
b– (39.0%)
EC (43.6%)
653 278
68Ga 1.13 b+ (88.9%)
EC (11.1%)
1899 836
89Zr 78.40 b+ (22.7%)
EC (76.2%)
902 396
124I 100.20 b+ (22.7%)
EC (77.3%)
2138 819
P. McQuade et al., Cur Med Chem, 2005
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
8/2/2018
3
PET Radiochemistry
11C, 18F, 124I
64Cu, 89Zr 68Ga
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Organic synthesis/
Radiolabeling
O
OAc
TsO
OAcAcO
AcOH2C
O
OH
18F
OHHO
HOH2C
K222, K18F
Hydrolysis:
Chelation/
Conjugation :R R
64Cu 64Cu
PET/CT HardwareRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
Current clinical PET performance: Spatial resolution ~5 mm
Sensitivity <pM
TOF PETRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
Early PET scanners utilized
coincidence detector timing to
localize events along a line-of-
response, however these
detectors were abandoned due
to poor sensitivity.
Philips introduced the Gemini TF
in 2006 taking advantage of
detector improvements to revisit
time-of-flight PET.
TOF resolution 300-500 ps
(9-15 cm)
S. Vandenberghe et al., EJNMMI Phys, 2016
8/2/2018
4
DOI PET
Dx
q
Increasing PET detector thickness is a
standard approach to improving
sensitivity. However, this comes with an
increase in parallax error.
DOI detectors are capable of measuring
the location of interaction of a 511 keV
photon within a scintillation crystal.
M. Ito, Biomed Eng Letters, 2011
M.F. Bieniosek et al., Phys Med Bio, 2017
M.S. Lee, Phys Med Bio, 2017
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Imaging Targets
Immune Cells
Tumor Cells
Cells
Proteins
Nucleic Acids
Molecules
Perfusion
Metabolism
Proliferation
Processes
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
FDG PET signal is dependent on:
• Vascular delivery
• Cell number
• GLUT expression
• Hexokinase expression
• Excretion pathways
Glucose-6-phosphatase
Slow!!!
Hexokinase
O
OHOH
HO
–PO4–OH2C
18F
Pyruvate
Phosphohexose
isomerase
OH
HO
–PO4–OH2C O CH2OH
18F
O
OH
18F
OHHO
HOH2C
GLUT
FluorodeoxyglucoseRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
8/2/2018
5
2-nitroimidazole uptake is dependent on:
• Vascular delivery
• Cell number
• Reductase expression
• Oxygen
• Excretion pathways
N N
NO2
R
N N
NHOH
R
N N
NH2
R
One Electron
Reductases
O2
Hypoxia PETRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
FD
GF
DG
FM
ISO
Pre
-txP
re-tx
Po
st-tx
D. Rischin et al., J Clin Onc, 2006
Hypoxia PET and PrognosisRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
Hypoxia PET and RT Response
0
0.5
1
1.5
2
2.5
3
3.5
4
0 10 20 30 40 50 60
No
rmal
ised
Po
st-R
T V
olu
me
Days Post Treatment
4 x 10Gy
0
0.5
1
1.5
2
2.5
3
3.5
4
0 10 20 30 40 50 60
No
rmal
ised
Po
st-R
T V
olu
me
Days Post Treatment
4 x 5Gy
R.S. Ali et al., PLoS One, 2015
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 30 35 40
No
rmal
ised
Po
st-R
T V
olu
me
Days Post Treatment
1 x 40Gy
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 30 35
No
rmal
ised
Po
st-R
T V
olu
me
Days Post Treatment
1 x 10Gy
p < 0.05
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
8/2/2018
6
Hypoxia PET and RT Response
Y. Qian et al., Int J Radiat Oncol Biol Phys, 2018
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Radiotracer Design
Small molecules• Require organic synthesis/radiolabeling
• Short blood half life/clearance time
• Can use short-lived positron emitters
• Unsuitable for conjugation to large labels such as chelators
Biologics and Nanoparticles• Typically expensive to manufacture
• Long blood half life/clearance time
• Require long-lived positron emitter
• Suitable for non-specific labeling, chelators
O
OH
18F
OHHO
HOH2C
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Quantitation
• Maximum intensity
• Minimum intensity
• Mean intensity
• Median intensity
• Integrated intensity
• 75th percentile
• 90th percentile
• Standard deviation
• Variance
• Skew
• Kurtosis
• ROI volume
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
8/2/2018
7
Variability in PET
F. Habte et al., Am J Nuc Med Mol Im, 2006
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Variability in PET
R. Jeraj et al., J Nuc Med, 2015
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Image SegmentationRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
Q. Black et al., Int J Rad Onc Biol Phys, 2004
8/2/2018
8
Validation
J. Murphy et al., Radiother Onc, 2011
Radiochemistry Imaging Technology Targets and Radiotracers Quantitation
Quantitative Imaging NetworkRadiochemistry Imaging Technology Targets and Radiotracers Quantitation
The QIN is an NCI-sponsored collective of 21 research teams spanning 19
institutions working to standardize imaging acquisition and analysis methods
in order to facilitate the widespread use of imaging as a quantitative biomarker
for cancer research and treatment.
Summary
• Radiochemistry of a large number of PET probes is
established and translatable.
• Clinical PET/CT scanners are capable of imaging
positron-emitting probes at sub-picomolar levels with
spatial resolutions of 4-5 mm.
• A variety of molecular and cellular processes are
imageable with PET.
• Current challenges to integration of PET images in
radiotherapy planning are establishment of robust
segmentation methods and the cost of multicenter
deployment and evaluation of these methods.