spect: new technologies and applications

AAPM 2012 Summer School on Medical Imaging using Ionizing Radiation

SPECT: New Technologies and Applications

Eric C. Frey, Ph.D., ProfessorDivision of Medical Imaging Physics

Russell H. Morgan Department of Radiology and Radiological Science


Disclosures

Johns Hopkins University Licenses an iterative reconstructioncode for SPECT to GE Healthcare. Dr. Frey is entitled to a shareof royalty received on sales by GE Healthcare of thisreconstruction code. The terms of this arrangement are beingmanaged by the Johns Hopkins University in accordance with itsconflict of interest policies


Learning Objectives

• Review current and future advances in instrumentation and reconstruction

• Describe new applications, especially those related to cancer therapy


Outline

• New Technologies– Instrumentation– Reconstruction

• New Applications


New Technologies: Instrumentation

• Collimators• Detectors• Photodetectors• Electronics• Multimodality Systems• Commercial Systems


Developments in Collimators

• Goal: improve resolution sensitivity tradeoff– Parallel-hole collimator Sensitivity ~ (FWHM Res)2

• Pinhole collimators• Slit/Slat collimators• Multi-focal collimators


Pinhole Collimators

θ

g de2 sin316Z 2

Rph B Z de

B (in object plane)

Rt Rph2

BZ

Ri

2

Field-of-view=F D ZB

Magnification M BZ


Pinhole vs. Parallel

• What is ratio of sensitivity for pinhole and parallel for equal resolution? gph

gp4k

1M 1

2

if dZL

2

MRi,ph 2


Pinhole vs. Parallel

• Pinhole sensitivity is better than parallel ifM > 0.42

and

• For fixed size object F, DR to be small• D is limit by floor on M• Thus, need small intrinsic resolution for pinhole

camera

dZL

MRi,ph


Multiple Pinholes

• Pinhole can use minification to reduce required size of detector (e.g., by factor of 2)

• Can thus use multiple pinholes (e.g., 4x) to image same size object

• Further improves sensitivity tradeoff


Limitation of Pinholes for Tomography

• Pinhole geometry is similar to cone-beam• Rotating pinhole in plan around object only

provides data sufficient to reconstruct central slice of object

• Requires more complicated orbits• Multiple pinholes partly remove this restriction

because they are not in the same plane


Slit-Slat Collimator

• Slit (like 1D pinhole) in transaxial direction

• Slats (like 1D parallel hole collimator) in axial direction

• Partial benefits of pinhole– Better resolution/sensitivity tradeoff– Magnification/minification in one

direction (multiple slits)

• Complete data for reconstruction (fan-beam)

Slit

Slat


Multifocal Collimators

• Converging collimators provide better sensitivity for same resolution

• Problem: Truncation• For small volumes of interest (VOI)

in a large object, multifocal collimators may offer benefits– Improved sensitivity in VOI– No truncation artivacts

• Require motion that keeps VOI in region of high sensitivity


Converging Collimators

• Converging collimators provide better sensitivity for same resolution

• Problem: Truncation


Multifocal Collimators

• For small volumes of interest (VOI) in a large object, multifocal collimators may offer benefits– Improved sensitivity in VOI– No truncation artifacts

• Require motion that keeps VOI in region of high sensitivity


New Detectors: CZT

• CZT (CdZnTe)– Semiconductor– Direct Conversion– Better energy resolution– Tailing:

• Trapping• Lower hole mobility

– Pixel sized determined by contact spacing• Charge sharing a challenge• Requires sophisticated per-pixel electronics (ASICs)

– Cost and growing large crystals still a challenge

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Pixelated Scintillators

• Cut scintillators into discrete crystals• Opaque light isolation• Resolution determined by size of crystal• Sizes < 1 mm• Pixel identification instead of position estimation


New Scintillators:

• LaBr3(Ce)– 65% higher light output than NaI(Tl)– Denser and similar effective Z (47 vs 50)– Substantially more expensive– Available in much smaller crystal sizes– Possibly useful for small, modular camera better

intrinsic resolution

SpecificGravity

Max nm

Index ofRefraction

Decay Time(µs)

Light Yield(photons/MeV)

Rel Yieldw/PMT

NaI(Tl) 3.67 415 1.85 0.23 38,000 1.00LaBr3(Ce) 5.08 380 1.9 0.016 63,000 1.65


Advances in Photodetectors

• Position Sensitive/Multi-Anode PMTs• P-I-N Photodiodes• Silicon Drift Detectors• Avalance Photodiodes• SiPMTs


Position Sensitive PMTs (PSPMTs)

• PMT with multiple outputs (4x4 to 16x16)• Output signals preserve spatial information about

photoelectron production• Similar properties to PMTs• Up to 50x50 mm active area (3x3 mm pixel size)• Can be tiled (~6 mm gaps)• Larger and lower efficiency than solid-state

alternatives


P-I-N Photodiode

• Reverse-biased P-I-N diode• Production of photoelectrons produces charge• No amplification, require very low noise preamp• Low noise (dark current)• Simple, stable, compact• Different absorption peak than PMT photocathodes• Available in arrays


Silicon Drift Detectors

• Series of electrodes in concentric rings creates drift region

• Photoelectrons drift toward anode in center of device

• Small anode gives low capacitance and good energy resolution

• Signal collected and amplified using integrated JFET provides low noise

• Arrays and large area devices have been produced


Avalanche Photodiodes

• Special designs to allow large reverse bias (100-2000 volts)

• Avalanche multiplication by impact ionization yields amplification of signal (gain of 100-1000)

• Sensitive to temperature and bias voltage fluctuations

• Available in arrays and position-sensitive versions


SiPM

• Arrays of many small photodiodes operating in GM-Mode– Each diode acts as binary photodetector with large gain– Using array of many photodiodes provides analog

behavior to scintillation light

• Relatively new• Modest size arrays available


Comparison of Photodetectors

PMT PIN PD SDD APD SiPMlog10(gain) 6‐7 0 0* Lo 6Noise Low Low Low Moderate LowPhotodetectionefficiency(420nm)

~20% 70% ~60% ~30%

FormFactor Bulky Compact Compact Compact CompactSensitivitytomagneticfields

High Low Possible Low Low

*Built‐inpreamp.


Advances in Electronics

• Move from analog to digital• Front-End Electronics• Improved position and energy estimation


Moving from Analog to Digital

γ Detector

hν Detector

ImageFormation

DigitalX,y,E Estimation

Analog Pulse Shaping

Digital Pulse ProcessingAnalog

X,y,E Estimation

ADC

ADC

ADC


Front End Electronics

• Achieving high intrinsic resolution requires processing more analog outputs from detectors

• This requires many more chains of analog and digital electronics

• Application specific integrated circuits are important for miniaturizing and reducing costs

• Field-programmable gate arrays (FPGAs) provide front-end digital logic

• Digital single processors often used to perform digital pulse processing


Improved Position and Energy Estimation• Traditional position and energy estimation

– Simple Anger equations– Apply energy, spatial, linearity corrections– Limits accuracy and precision of energy and position

estimates– ‘Dead area’ at adge of detector

• Modern approaches– Treat as estimation problem– Apply maximum likelihood techniques– Better energy and position estimates– Greater uniformity– Larger useful FOV


Multimodality: SPECT/CT

• First generation (GE Hawkeye):– Low power CT– 1-4 slice detector

• Slice thickness: 2.5-10 mm

– Attached to Slip-Ring SPECT Gantry

• 2.5 rpm->up to 9 minutes to acquire data for entire SPECT FOV

• Breathing artifacts

X-rayTube

X-rayDetector


SPECT/CT

• Second Generation (Philips Precedence)– CT scanner joined to

SPECT system– Diagnostic-quality CT

and acquisition times– Large footprint


SPECT/CT

• Third Generation (Siemens Symbia T, GE NM/CT 670)– Integration of XCT and SPECT– Smaller footprint than 2nd

generation– Diagnostic quality CT


SPECT/CT

• Flat Panel CT and x-ray source (Philips BrightView XCT)– High resolution– 80 mA tube– Not diagnostic CT quality

• Other (Digirad Cardius X-ACT)– Pb x-ray fluorescence source and NM detectors– Fan-beam geometry– Low x-ray flux/low resolution– Suitable for attenuation map


Multimodality: SPECT/MR

• Semiconductor detectors or solid state photodetectors

• Collimators a challenge (tungsten epoxy, tungsten beads, …)

• Investigational for small animals• Potential for true simultaneous imaging

– Monitor motion– Dynamic imaging

• At developmental stage


Novel Commercial Systems

• Digirad Cardius X-ACT– Three cameras with solid-state photodetectors, fan-beam

collimators transmission CT using x-ray fluorescence source

• GE NM530/570– Pinhole, CZT

• D-SPECT– Scanning small FOV CZT detectors with parallel-hole

collimators

• Cardiarc HD– Multiple moving slit/slat collimators , curved NaI

detector


Digirad Cardius X-ACT

Modular solid state detectorpixelated CsI(Tl) scintillator

photodiode array

Figures courtesy of C. Bai and R. Conwell, Digirad

3 Camera, fan-beam collimators, seated imaging position


Digirad Cardius X-ACT

Figures courtesy of C. Bai and R. Conwell, Digirad

Sample TCTImages


GE Discovery NM 530c & NM/CT 570c

• CZT detectors (2.5 mm pixels)• Multiple (~16) pinholes• No rotation required• True 3D dynamic SPECT• Improved energy resolution• >5x reduction in scan time

99mTc: 140 keV

123I: 159 keV

50 100 150 keV 200

point sources in air Alcyone 6.2% Anger 9.5%


Spectrum Dynamics DSPECT

• 10 CZT detectors (2.5 mm pixels)

• Parallel-hole collimation• Detectors moveindividually• Very high sensitivity (10x?)

Images courtesy of Spectrum Dynamics


Spectrum Dynamics D-SPECT

64 elements ~160 mm

16 elements ~40 mm

2.46 mm

2.46 mm

5 mm thick CZT Detector Element

1024 elements

per column

Detector Column

Column Collimator

Detector Array

Direct conversion of photon energy to voltage pulse

Figures courtesy of Spectrum Dynamics


Cardiarc HD-SPECT

• Conventional (curved) NaI/PMT detector

• Slit/slat collimator (fan beam geometry)

• Resolution determined by slit width and slat spacing

• Multiple slits (equivalent to multiple cameras)

• Only slats (aperture arc) move

• Seated imaging position

6 slitsHorizontal

Slats (one per slice)


Outline




Developments in Reconstruction

• Quantitative SPECT• Simultaneous Dual Isotope SPECT• Quantitative Bremsstrahlung SPECT


Quantitative SPECT

• Requires– Attenuation and scatter compensation– CDR compensation desirable for small objects and high

energy photons– Calibration

• Sensitivity measurement (source in air)• Calibration phantom

• Applicable to a range of radionuclides• Technologies available, but not typically

implemented by manufacturers


Quantitative SPECT with In-111

NC A AS AGS ADS Atn Map

NC=No CompensationA=Attenuation Compensation

AD=Attenuation and CDR Comp

AS=Attenuation and Scatter CompensationADS=Attenuation, CDR and Scatter Comp

B. He, Y. Du, X. Song, W.P. Segars and E.C. Frey, “A Monte Carlo and physical phantom evaluation of quantitative In-111 SPECT,” Phys Med Biol, 50(2005): 4169-4185, 2005.

GE Millenium VG w/Hawkeye SPECT/CT system, MEGP Collimator


Quantitative SPECT with In-111

Organ NoComp

AttenComp

Atn+Scat

Comp

Atn +CDR

+ ScatComp

Atn +CDR

+ Scat+ PVC

Heart -77.60% 24.63% -11.76% -3.72% -2.11%

Lungs -62.78% 31.39% -0.96% 4.23% 6.45%

Liver -74.38% 29.22% -7.47% 2.71% 4.14%

20.6 ccsphere -78.88% -14.85% -29.81% -3.36% -1.97%

5.6 ccsphere -88.24% -51.53% -56.75% -21.55% -11.95%

% Error in total activity estimation: (true-estimate)/true x 100%

PVC using pGTM method


128 projection views Acquisition time: 40s / view

Heart Chamber Myocardium Large

SphereSmall

Sphere Background

Volume (ml) 59.7 115.3 17.5(r =1.61 cm)

5.7(r =1.11 cm) 9580

Activity(mCi) 0.562 0.471 0.136 0.044 8.15

Activity concentration(mCi/μl)

9.38 4.08 7.77 7.72 0.851

I-131 Physical Phantom

• Philips Precedence SPECT/CT system with HEGP collimator


I-131 Physical Phantom

(%) Heart Large sphere(r = 1.61 cm)

Small sphere(r = 1.11 cm)

AGS -15.21 -26.12 -32.72

ADS 4.75 -17.63 -25.77

ADS+Dwn+ -5.20 -21.10 -31.17

ADS+Dwn+PVC* -2.88 -15.49 -19.28

Percent errors of activity estimates for Anthropomorphic torso phantom

50 iterations 24

subsets/iteration

AGS ADS ADS + Dwn ADS+Dwn+PVE+DWN=model-based downscatter compensation*PVC=reconstruction-based PVC compensation


Non-specific background uptake

Left putamenRight putamen

Left caudateRight caudate• GE Millennium VG/Hawkeye

(5/8” thick crystal)• LEHR Collimator

• 128 views/360°, 128*128 projection w/ 0.24 cm pixels • CT attenuation maps

• Manually defined VOIs using registered MR Images

• Activity concentrations:• Bkg: 110 kBq/ml

• Left Caudate: 212 kBq/ml• Left Putamen: 154 kBq/ml

• Right Caudate: 1770 kBq/ml• Left Putamen: 222 kBq/ml

Quantitative SPECT with I-123RSD Striatal Phantom

Y. Du†, B.M.W. Tsui, E.C. Frey, “Model-based compensation for quantitative 123I brain SPECT imaging,” Phys Med Biol, 2006, Vol. 51(5): 1269-1282, 2006.


OS-EM w/AttenuationScatter &

CDRF Compensation Post-Reconstruction

pGTM PVC

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Quantitative SPECT with I-123


Simultaneous Dual-Isotope SPECT

• Requires– Compensation for cross-talk

• Scatter in body• Scatter (and Pb x-rays) in collimator-detector

– Publications on various pairs of radionuclides• Tc-99m/Tl-201 (rest/stress perfusion, brain tumors)• Tc-99m/I-123 (perfusion/innervation,

perfusion/receptor, …)• Tc-99m/In-111 (blood pool, antibody)• Tc-99m/F-188 (perfusion/viability)• In-111/I-131 (therapy)


MIN0 30 60

EX

2 mCi Tl

0

1

2

3

4

5

6

40 80 120 160 200Energy (keV)

Det

ecte

d C

ount

s

Tl

10 mCi Tc

Tc

Dual IsotopeSPECT

TcTl

Simultaneous Dual Isotope Rest/Stress MPS


Tc-99m/Tl-201 Dual Isotope SPECTValidation in Dogs

Sep Acq

DISA-No Comp

DISA-w/ Comp

Comparison of CircumferentialProfiles for One Dog

Correlations betweenIshemic/Non-Ischemic

Activity Ratios for 25 Dogsfor Imaging and Ex Vivo

Measurements


Quantitative Bremsstrahlung SPECT

• Continuous and broad energy spectrum

Tc-99m90Y

bremsstrahlung


Quantitative Bremsstrahlung SPECTPhantom Study

Large sphere Medium sphere Small sphere

Error -7.0% -9.7% -10.2%

Error = (EstimatedActivity – TrueActivity) / TrueActivity ×100%


True Activity Distribution

MERw/o added noise

OS-EM w/ attenuation compensation alone

MERw/ added noise

Total activity: 80 mCi (2.96 GBq)Imaging time: 30 min10 iterations with 16 subsets per iterationTwo rightmost images were filtered using a Butterworth filter.

Quantitative Bremsstrahlung SPECTSimulation Study


Error = (EstimatedActivity – TrueActivity) / TrueActivity * 100%

Lung Spleen Kidneys Liver Heart

MER 100-500keV 11.9% -5.9% -3.2% -1.6% -2.4%

attenuation compensation 324.4% 121.5% 400.9% 254.1% 133.8%

Errors in organ activity estimates at 200th iteration (16subsets per iteration) for data w/o added noise.

Quantitative Bremsstrahlung SPECTSimulation Study


Quantitative Bremsstrahlung SPECTPatient Study

BremsstrahlungSPECT

BremsstrahlungQSPECT

MAAQSPECT


Outline




Common Imaging AgentsRadiopharmaceutical Applications99mTc sestamibi/tetrofosmin myocardial perfusion, breast cancer, parathyroid201TlCl Myocardial perfusion, glioma99mTc MDP Bone metasteses/stress fractures99mTc DMSA Renal function99mTc MAG-3 Citrate Renal function99mTcO4- Salivary glands, thyroid, parathyroid99mTc Red blood cells Blood: bleeding, cardiac blood pool/ejection fraction99mTc microaggregated albumin (MAA) pulmonary perfusion

99mTc sulfur colloid reticuloendothelial system, lymphatic system, gastric emptying

Xe-133 pulmonary ventilation111In oxime (label stem cells, white blood cells, eggs) stem cell tracking, infection, gastric emptying111In pentetreotide (Octreoscan) somatostatin analog: neuroendocrine tumors

Ga-67 cintrate lymphoma, inflammation

I-123/I-131 MIBG neuroendocrine tumors (neuroblastoma/pheochromocytomas), cardiac ennervation

I 123/I 131Cl Th id


New Applications

• Myocardial Innervation Imaging• Neuroreceptor Imaging• Targeted Radionuclide Therapy Treatment

Planning– Radioimmunotherapy– Peptide recepter radionuclude therapy– Radioembolization/Microsphere brachytherapy


Myocardial Innervation Imaging

• I-123 MIBG (Iobenguane/AdreView)– Noradrenaline analog– Used to image cardiac innervation

• Increased washout rate in heart failure• Mismatch between innervation and perfusion post-

MI


Neuroreceptor Imaging

• I-123 Ioflupane (DaTscan)– Targets presynaptic dopamine

terminals– Applications in diagnosis of

Parkinson’s disease– Reduction or asymmetry in uptake

in striatum


Targeted Radionuclide Therapy

• Treatment planning– Goal: estimate administered activity (AA) to provide

therapeutic effect and avoid toxicities– Method:

• Estimate dose to organs and tumors from known AA of a planning dose

• Use this with RTD to calculate therapeutic AA


Targeted Radionuclide Therapy

• Treatment planning– Complications

• Organ anatomy and biokinetics are patient dependent• Radiation transport is patient dependent• Dose rate is time varying and spatially nonuniform

– Approach• Use quantitative imaging to measure biodistribution

of planning dose as a functionof time for each patient• Use radiation transport calculation to calculate dose

to organs, tumors or voxels• Apply radiobiology-based concepts from external

beam therapy (RBE, EUD, NTCP, TCP)


TRT Treatment Planning Flow Chart

Administer Planning

Dose

Measure Distribution over Time

Calculate Dose (Dose Rate) Distribution

Calculate Therapeutic

Activity

Administer Therapeutic

Dose


MIRD Formalism (Organ Dosimetry)

DoseT As S(OT Os )s

All SourceOrgan

S-valueTime-Integrated Activity

A A(t)dtt0


Time-Integrated Activity and Residence Time

A : Time-integrated activity (MBq sec)A0 : Injected activity (MBq) : Residence Time (sec)

A A t dtt A0

Activ

ity A

(t)(M

Bq)

A

Time t (sec)

where A / A0


SPECT Residence Time Estimation

ResidenceTime

CTSPECT

Proj.

Curve Fitting

SPECTActivity

Estimation

0 hr

4 hr

24 hr

72 hr

144 hr0

0.02

0.04

0.06

0.08

0.1

0.12

0 50 100 150Time (hours)

0

A tA

organ

0

0.02

0.04

0.06

0.08

0.1

0.12

0 50 100 150Time (hours)

0

A tA

organ


Voxel Dosimetry

Measure Activity

Distribution at Set of Times

Calculate Dose Rate in Each Voxel at Each

Time

Register Dose-Rate Images

Integrate Dose Rate over Time

Integrate Dose Rate over

Organ


Summary of Imaging Requirements for TRT Treatment Planning

• Organ Dosimetry: organ activity estimates at each time point

• Voxel Dosimetry: requires registered 3D activity distribution estimates at each time

• Activity can be estimated from PET or SPECT images acquired at eac time

• Radionuclides imaged often have non-ideal imaging properties


Radioimmunotherapy

• Non-Hodgkins Lymphoma – I-131 tositumomab (Bexxar)

• Dosing based on whole body dose from planar imaging

– In-111/Y-90 ibritumomab tiuxetan (Zevalin)• Weight-based dosing• Imaging no longer required• Approved as first-line consolidation therapy

– Bone marrow is dose-limiting– Clinical trials of myeolablative therapy regimens

• Lungs (Bexxar) or liver (Zevalin) dose limiting• Imaging required for treatment planning


Peptide Receptor Radionuclide Therapy

• Smaller moleculues– More rapid uptake and clearance– Kidneys dose-limiting

• Lu-177 or Y-90 Dotatate– Binds to somatostatin receptors– Targets neuroendocrine tumors (NETs)– Therapy planning using In-111 SPECT or Ga-68 PET

labeled agent– Currently in clinical trials (extensive experience in

Europe)


Radioembolization of Liver Cancer

• Y-90 labeled microspheres– Delivered through cather to hepatic artery– Hepatic artery supplies provides larger blood flow to

tumors than normal tissue

• Tc-99m Macroaggregated Albumin (MAA) used to evaluate potential for extrahepatic radiation

• Dosing scheme depends on product• Recent AAPM Dosimetry Recommendations

– Dezarn et al, Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies , Med Phys, vol 38(8), 2011, pp 4824-45.


Radioembolization of Liver Cancer

• Commercial Products– TheraSphere (glass microspheres containing Y-90)

• Activity based on average dose to treated volume• Approved for treatment of hepatocelluar carcinoma (HCC)

– SIR-Spheres (resin microspheres containing Y-90)• Several dosing schemes (some include dosimetry using

partition model)• Lower specific activity -> larger number of spheres-> greater

embolic effect• Approved for metastatic colorectal cancer (mCRC)


Evaluation of Therapeutic Response• Various agents are available that target cancers

– I-123 MIBG • Noradrenaline analog• NETs such as neuroblastoma, phaeochromocytoma

– In-111 Octreotide• somatostatin receptor• Various NETs

– Tc-99m MDP• Bone metastases and cancers

• Quantitative imaging may be useful to follow treatment response


Evaluation of Therapeutic Response


Conclusions

• New instrumentation technologies are on the horizon that have the potential to improve the quality of SPECT images– Collimation– Detectors

• Technology is available to produce quantitative images for a variety of applications

• New agents have been introduced• New applications cancer therapy include targeted

therapy treatment planning and monitoring treatment response

spect: new technologies and applications

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