Quantitative PET/CT Imaging for Drug Discovery, Clinical Trials, and Individual Response to Therapy Paul Kinahan, PhD Director of PET/CT Physics Imaging Research Laboratory, Department of Radiology University of Washington, Seattle, WA AAPM Annual Meeting July 26-30, 2009 Anaheim, CA Updated 9 July 2009 P. Kinahan UW 2 PET/CT Applications and Challenges Primarily for Cancer Imaging -- works very well • Diagnosis and staging Expanding Areas -- with significant challenges • Radiation treatment planning using PET and CT • Neurological imaging • Cardiac imaging • Assessment of therapeutic response
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Quantitative PET/CT Imaging for DrugDiscovery, Clinical Trials, and
Individual Response to Therapy
Paul Kinahan, PhD
Director of PET/CT PhysicsImaging Research Laboratory, Department of Radiology
University of Washington, Seattle, WA
AAPM Annual Meeting July 26-30, 2009 Anaheim, CA
Updated 9 July 2009 P. Kinahan UW 2
PET/CT Applications and Challenges
Primarily for Cancer Imaging -- works very well• Diagnosis and staging
Expanding Areas -- with significant challenges• Radiation treatment planning using PET and CT• Neurological imaging• Cardiac imaging• Assessment of therapeutic response
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Do Numbers Matter in PET Images?
• The answer to the question “Is quantitation necessary for clinical oncologicalPET studies interpreted by physicians with experience in interpreting PETimages?” is “no.”
• Image quantitation will become increasingly important in determining theeffect of therapy in many malignancies.
Elevated uptake of FDG (somehow related to metabolism)
R Edward Coleman Eur J Nucl Med (2002) 29:133–137
Updated 9 July 2009 P. Kinahan UW 4
Castell and Cook, British Journal of Cancer (2008)
Pretherapy
1 wkimatinibtherapy
CT PET/CT
PET SUV5 -> 1.8
Response to therapy of liver met gastric GIST
• No morphological change in the metastasis
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Times to Relapse after Neoadjuvant Chemo-radiotherapy compared to PET/CT for NSCLC
Pöttgen, et al Clinical Cancer Research, 2006
Time to extracerebral progressionPartition ratio: SUVmax*(t2)/SUVmax*(t0) ≤ 0.5
P < 0.05
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• "The favorable experience to date is beginning to supportthe use of PET as a surrogate end point in trials that areaimed at testing or comparing the efficacy of new drugsor treatments" [Juweid & Cheson NEJM 2006]– When numbers matter in evaluating response, understanding and
reducing scanner bias and variance improves the statisticalpower of studies
• Evaluation of new therapies requires multicenter studiesfor patient recruitment– Pooling results between different PET/CT scanners requires
knowledge of biases between scanners to improve the statisticalpower of studies
• Until recently, there have been few systematic efforts tounderstand or improve quantitative accuracy, precision,and stability between multiple sites.
Summary of Issues for Quantitative PET/CT Imaging
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What do PET scans Measure?
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How it works: Positron Emission
Radioactive decay• unstable atomic nuclei due to too
many protons relative to thenumber of neutrons
• decays to stable form byconverting a proton to a neutron
• ejects a 'positron' to conserveelectric charge
• positron annihilates with anelectron, releasing two anti-colinear high-energy photons
npnp
n
pnp n
pn
pn p
p
pn
p n
pn
p
n
p n npnp
n
pnp n
pn
pn p
n
pn
p n
pn
p
n
p n
~2 mm
18F 18O
~180 deg
E = mc2
= 511 keV
β+
e-
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How it works: Timing coincidence
Δt < 10 ns?
detector A
detector B
recordpositrondecayevent
scannerFOV
β+ + e-
annihilation
reconstruct imageof SUV values
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PET Scans Measure Activity Concentration
• If everything goes well, the role of the PET scanner is tomeasure the radioactivity per unit volume
• Typically measured as kBq/ml or µCi/ml
10 mCi = 370 MBq 70 kg water = 70 L inject
concentration = 370,000 kBq / 70,000 ml = 5.3 kBq/ml
suppose there is a very smallobject that takes up 5x thelocal concentration, so itsconcentration = 26.5 kBq/ml
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What if there are different activities ordistribution volumes?
• Injecting different amounts or changing the volume will changethe concentration
10 mCi = 370 MBq inject
concentration = 5.3 kBq/ml
5 mCi = 185 MBq inject
concentration = 2.8 kBq/ml
10 mCi = 370 MBq inject
concentration = 10.6 kBq/ml
35 kg = 35 L
26.5 kBq/ml
13.3 kBq/ml
53.0 kBq/ml
The hot spot hasdifferent uptakevalues in kBq/mleven though ithas the samerelative uptakecompared tobackground
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Standardized uptake values (SUVs)• Normalize by amounts injected per volume (i.e. weight) to get
the same relative distribution with SUV = 1.0 for a uniformdistribution
10 mCi = 370 MBq inject
SUV = 5.3 kBq/ml / (370MBq/70 Kg) = 1.0 gm/ml
5 mCi = 185 MBq inject
SUV = 1.0 gm/ml
10 mCi = 370 MBq inject
SUV = 1.0 gm/ml
35 kg = 35 L
SUV = 5.0
SUV = 5.0
SUV = 5.0
The hot spot nowhas the same SUVuptake valuesindependent inactivity injected orvolume ofdistribution (i.e.patient size)
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Measuring uptake: kBq/ml vs SUVSame scale inunits of kBq/ml
Same scalein units ofSUV [g/ml] Liver values
look moreuniformbetweenpatients
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Sources of Error in SUV Values
It is important to minimize SUV errors for serial studies (excluding artifacts)Some potential sources of error are:• Determining that blood glucose levels are within range• Changing dose uptake time• Scanner calibration and cross calibration with dose calibrator• Dose assay for each patient, which uses several pieces of information, all of which have
to be correct:• Correct clock settings for scanners, injection times, and assay times for correct
calculations of radioactive decay and dose uptake periods• Changing reconstruction or other processing protocols• Changing analysis methods: How ROIs are determined and whether max or mean SUV
values are reported• Weight is typically used as a surrogate for volume of distribution, but can also be further
normalized for lean body mass or body surface area, which have to be estimated
SUV =PET
ROI
!DINJ/ !V
PET = measured PET activity concentrationD' = decay-corrected injected doseV' = surrogate for volume of distribution
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Biological Effects
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Effect of blood [Glu] on SUVs of liver mets fromcolorectal carcinoma
• 8 patients w/ 20 liver metastases by CT (size 10-75 mm, mean 32 mm)• Fasting FDG-PET scan followed 2 days later by glucose-loaded scan (i.v.
Illustration of impact of changes indose uptake duration
• The same study at different post-injection times will give different SUVs• This problem is worse when two different studies are compared looking for an
Variations are introduced by the scanner type,acquisition protocol, calibration differences,processing (e.g. image reconstruction methodor smoothing) and ROI definition method.
averaged coefficients of variation
mean SUV: 8.6%, max SUV: 11.1%
Plots of recovery coefficient (RC) = measured in ROI/true
Kinahan et al 2009 SNM
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Effect of changing post-reconstructionsmoothing
10 mm smoothing4 mm smoothing 7 mm smoothing
SUVmax for 1 cm spheres
3.4
3.7
2.1
3.2
1.62.9
SNM Chest phantom, 2 iterations, 28 subsets - True SUV (average) is 4.0
Effect of Analysis Method
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Typical Object-Based ROIs:Size and placement based on CT and/or PET
efficiency normalization• Resolution loss: aka partial volume errors• Reconstruction method (smoothing and iterations)• Analysis method: ROI definition method and SUV mean vs max• Artifacts
– patient motion: respiratory and other– incorrect SUV scaling– Attenuation correction with CT: truncation, motion, incorrect
scaling, general CT artifacts• Care should be used if serial studies rely only on lesion SUV