Download - Automated Software Framework for Voxelized Absorbed Dose Estimation in Radionuclide Therapy
Automated Software Framework for Voxelized Absorbed Dose Estimation in
Radionuclide Therapy P Jackson, PhD; J Beauregard, MD, MSc; T Kron, PhD, DIPLPHYS; M S Hofman, MBBS; R Hicks, MBBS
Centre for Molecular Imaging
Peter MacCallum Cancer Centre
East Melbourne, Australia
Purpose:
• Accurately map distribution of radiation dose to healthy & target tissues in Peptide Receptor Radionuclide Therapy (PRRT)– Treatment given over 4 or more
cycles– Opportunity to adjust prescription
based on absorbed dose estimate?
Small volume disease, limited
absorption in lesion, high
SUV in kidneys & spleen
Bulky & highly octreotate-avid
liver lesions, limited uptake
observed in healthy organs
Internal Emitter Dosimetry• Radionuclide Dosimetry as function of:
– Pharmacokinetics• Biological half-life, uptake & clearance (multiple phases)
– Physical half-life– Emission particles
• Type & energy– Absorbing medium
• Generally soft-tissue (high-dose regions)
• MIRD: OLINDA/EXM (Gold Standard)– Male/Female/child MIRD phantoms with customizable organ
mass– Absorbed dose values accurate when considered over large
population• Difficult to account for absorbed dose to tumour/target
volume• Not intended for individualised dosimetry
“NOTE: This code gives doses for stylized models of average individuals -
results should be applied with caution to specific subjects.”
Not an issue for short-range beta emitters, though• Significant Manual input• No accounting for sub-organ kinetics (renal pelvis vs.
cortex)
Voxelized Registration and Kinetics (VRAK)• In-house dosimetry protocol based on
serial SPECT/CT:– Deformable Registration– Automatic Kinetics fitting & activity
integration– Voxel S-Values (EGSnrc)– Output: dicom dose & cumulated
activity volumes, data file with per voxel kinetics parameters
– All scripted• Called from command-line w/text input
file• Python-based (pydicom, numpy)
– Open-source dependencies– Cross-platform (Win, Mac, Unix)
4-Hour
Fused SPECT/CT
24-Hour
Fused SPECT/CT
72-Hour
Fused SPECT/CT
Image Registration
4-Hour CT
Fused to
4-, 24- & 72-hour
SPECT
Voxelized Kinetics
4-Hour CT
Fused to
Cumulated Activity
Image
(Bq*Hr/mL)
Voxel S-Value & Gamma
Convolution Kernel
4-Hour CT
Fused to
Absorbed Dose
Image
(mGy)
Curve Fitting
parameters per
voxel
Visual Analysis
Video:
Interpolated activity &
Cumulated activity
Quantitative SPECT CT:
• 177Lu: 112 keV (6.2%) & 208.4 keV (10.4%) γ’s, 497 keVmax β- (100%)
• 3 Quantitative SPECT/CT series– 4, 24, 72 hours Post-injection– SPECT quantitation previously
calibrated*• 177Lu-specific attenuation & dead-time
correction– 2 couch position (chest+abdomen)
• Full datasets for 28 LuTate Rx’s (18 different patients) used for validation
*Beauregard, J.-M. et al., 2011. Quantitative (177)Lu SPECT (QSPECT) imaging using a
commercially available SPECT/CT system. Cancer imaging: the official publication of the
International Cancer Imaging Society, 11, pp.56-66.
Image Registration : SPECT/CT• Sequential Rigid & Deformable
– Elastix* (ITK-based, adjustable parameters, scriptable)
• Multi-resolution B-Spline Deformation• Mutual Information Metric (80%) +
deformation penalty (20%)• Robust, few ‘optical flow’-type artifacts
– Co-register Anatomical (CT) volumes• Warp functional (SPECT) images
– Inspect registered SPECTs• Apply translation where necessary
– Output: 3 SPECT volumes aligned to 4-hour CT (fixed image) array
space• Same resolution & origin (Image Position
Patient
* Klein, S., Staring, M. & Pluim, J.P.W., 2007. Evaluation of optimization methods for
nonrigid medical image registration using mutual information and B-splines. IEEE
transactions on image processing : a publication of the IEEE Signal Processing
Society, 16(12), pp.2879-90.
4-hour 24-Hour Difference/Overlay
Post-registration SPECT/CTs:
4-hour: Red
24-hour: Green
Aligned Images Voxelized Kinetics• 3 Co-registered SPECT Series 1 Volume
(cumulated activity)– Read Time P.I. From DICOM header– Decay-correct activity values
• Voxel-by-voxel– Analytical fit of 3-phase exponential
pharmacokinetics• 1 Uptake, 2 Clearance
– -A1=A2+A3 (C=0 at t=0)– K1>k2>k3
• Ignore values ~0 (out of patient or not relevant for dosimetry)
• Adjust unrealistic, noisy values• Calculate for slope (as exponential) between
measurements– Solve k3, A3– Solve k2, A2– Solve k1– Limit Rate constants (k) to realistic range
where necessary• Weighted for final time point• Single-threaded, but efficient (50-100x
improvement over iterative curve-fitting routine: Scipy.Optimize)
• 25M Voxels/Hr– 2-Position Chest/Abdo SPECT: 1.5 Hours
tktktk eAeAeAC *3
*2
*1
321 ***
4 Hr SPECT 24 Hr SPECT 72 Hr SPECT
Cumulated Activity
Kinetics Processing• 3x SPECT Array of kinetics parameters
(A1, k1, A2, k2, A3, k3): [x,y,z,6]• Integrate decay-adjusted curves for
disintegrations per unit volume– Output: Cumulated Activity (Bq*Hrs)/(mL)– Save as dicom (.dcm) or ITK (.mhd/.raw) file
• Visual Output– Can be use to create image sequence of
uptake & clearance• Arguments: slice #,
projection (axial, sagittal, coronal), time window, # of frames
– Save frames at times t• Interpolated Activity• Interpolated cumulated activity
– Informative evaluation of relative uptake & clearance
• Contribution of activity at time t to total # of disintegrations
Activity t=0-100Hrs Cumulated Activity
(Bq/mL) (Bq*Hr/mL)
Dose CalculationCumulated Activity Absorbed
Dose– EGSnrc Simulation for beta- and
photon components of 177LuDecay
• All tissue assumed to be H2O equivalent• Voxel S-Values for beta- component
– Local energy deposition (only voxel self-dose)
– Agreement with publishedS-values*
• Long-range Gamma Voxel Dose Kernel– Low-resolution (high-efficiency)
» 1.6*1.6*2.0 cm Voxels– Kernel calculated by dosxyz (EGSnrc)– Convolved through activity array
*Lanconelli, N. et al., 2012. A free database of radionuclide voxel S values for the dosimetry
of nonuniform activity distributions. Physics in medicine and biology, 57(2), pp.517-33.
Radiation Absorbed Dose (point spread function, in H20)
1.00E-19
1.00E-17
1.00E-15
1.00E-13
1.00E-11
1.00E-09
1.00E-02 1.00E-01 1.00E+00 1.00E+01 1.00E+02
Radial Distance (cm)
Abs
orbe
d D
ose
(Gy/
deca
y)
Beta DoseGamma DoseTotal Dose
Point Spread Function
EDKnrc
Sphere
Model
VSV Calculation
dosxyz (EGSnrc)
Beta- Range vs. SPECT Resolution• Range of beta electron transport shorter than range of
SPECT Partial Volume effect– SPECT Partial Volume effect for point source:
• Gaussian spread w/FWHM 7-15 mm*– Absorbed Dose range for 177Lu beta-: 1-2 mm– Activity heterogeneity clearly evident in PET
• \ Beta- energy from apparent activity (as seen on SPECT) considered to be deposited locally (in same voxel)
177Lu-Octreotate SPECT Imaging
24 Hrs PI
68Ga-Octreotate PET Imaging
1.1 Hrs PI
* Gear, J. et al., 2011. Monte Carlo
verification of polymer gel dosimetry applied
to radionuclide therapy: a phantom study.
Physics in Medicine and Biology, 56, p.7273.
Gamma Dose• Small proportion of total dose
– ~5-20% depending on region• Greater Range
– Soft dose gradient• Dose Kernel from DOSxyz
– Low-resolution (voxels 1.6*1.6*2.0 cm3)
– Long range (21 cm max)• In processing:
– Convolve through activity array– Combine with beta component for total
absorbed dose• Output can be written as dose volume
from beta-, gamma, combined
– maintains alignment to CT dataBeta
- dose
(87%)
Gamma dose
(13%)
Gamma Kernel (dosxyz)
Convolved Cumulated Activity Array
Validation Methods• Coregister Serial SPECT/CT Volumes• Segment fixed CT volume in each
study• Lower Large Intestine, Small intestine,
Stomach, Upper Large Intestine, Heart , Kidneys, Liver, Lungs, Muscle, Pancreas, Marrow, Spleen, Bladder, Lesion
• OLINDA Analysis– Apply segmentation to serial SPECT
scans– Input mean organ activity values– Compute mean organ dose
• VRAK Analysis– Apply segmentation to dose volume– Report Mean organ dose
Results: Cumulated Activity & Organ Doseas compared to OLINDA
*Compartmental Organs in MIRD model (separate source & target regions; contents + wall)
At Risk organs (Somatostatin Analog PRRT)
Results: Cumulated Activity & Organ Doseas compared to OLINDA
• Estimate of decays and total dose to kidneys, liver & spleen in the range of 5% with respect to conventional technique
• Segmenting both contents and wall of compartmental organs overestimates dose by 30-100%
– Greatest discrepancy in bladder– Similar effect observed in marrow
• Comparable estimate of cumulated activity, but higher dose in segmented volume
• Geometric effect accounted for by organ S-Value– Selective segmentation required
• But susceptible to partial volume effect
Compartmental Organ Model
Source Volume
Tissue (Bladder Wall)
MIRD Bladder:
Ellipsoid Source (Radius x,y,z: 4.71, 3.21, 3.21 cm)
Outer Wall (Tissue) 2.5 mm thickness
Results: Organ S-Value
• VRAK beta- VSV + gamma kernel closely matches MIRD S-values for solid organs
– Common at risk organs in PRRT– Lesions are solid volumes too
• Mean Lesion Dose (between all studies): 24.5 ± 9.7 Gy
– ~10:1 ratio lesion to kidney dose (10.1±6.0)• Fraction of total patient dose from beta-
emission: 87.1±0.75%• MIRD model better suited to compartmental
organs– But MIRD schema does not account for self-
dose to GI wall, only from contents• Relevant in somatostatin analog therapy
Discussion• Efficient, automated tool for PRRT dosimetry using
serial functional images– Close agreement with OLINDA in both kinetics and
dose estimates at organ level for 177Lu-octreotate dataset
– Smooth, predictable kinetics estimation• No artifacts or noise from processing• Visually clear dosimetry data that can be overlaid with CT
volume– Non-specific in design: can be applied to other
isotopes, quantitative imaging (PET)• Need to know: physical half-life, isotope VSV & Gamma
Kernel (dosxyz)– Personalized dosimetry data from initial cycle may be
used to inform subsequent therapies• Radionuclide dosage• Extended renal-protective measures• Monitor relevant biochemical markers for at-risk organs
HU
mGy
4-Hour CT
VRAK Dose
Discussion• Limitations:
– Homogenous tissue (H2O) assumed– Resolution of SPECT (1-2 cm)
• Detection of highly heterogeneous uptake?• Disintegrations in tumour spread across larger
volume– Reduces estimate of absorbed dose in lesion
– Registration accuracy varies• In range of 5 mm for most organs
– Other algorithms (Demons, etc) can be more precise, but prone to artifacts
• Inconsistent breath hold can shift activity near diaphragm (liver & metastases, spleen)
– Kinetics Fitting may overestimate cumulated activity to organs with transient uptake at early time point (bladder, bowel)
• Not observed in critical organs, tumour volumes
Anatomical Volume
Approx. Margin of SPECT volume
Project Homepage• VRAK: http://code.google.com/p/vrak-dosimetry/
– Dependencies:• Elastix (http://elastix.isi.uu.nl/about.php)• Python 2.7 (http://www.python.org/download/releases/2.7.3/)• Pydicom (0.9.7) (http://code.google.com/p/pydicom/downloads/list)• Numpy (1.6.2) (http://sourceforge.net/projects/numpy/files/)• For Video:
– ffmpeg (compiled from source) (http://ffmpeg.org/download.html)– PIL (http://www.pythonware.com/products/pil/)– Matplotlib (1.1.1) (
http://sourceforge.net/projects/matplotlib/files/matplotlib/matplotlib-1.1.1/)– Recommended Viewer: 3D Slicer (http://www.slicer.org/)
References• Beauregard, J.-M. et al., 2011. Quantitative (177)Lu SPECT (QSPECT) imaging using a commercially available
SPECT/CT system. Cancer imaging: the official publication of the International Cancer Imaging Society , 11, pp.56-66.
• Lanconelli, N. et al., 2012. A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions. Physics in medicine and biology, 57(2), pp.517-33.
• ICRP, 1983. Radionuclide Transformations: Energy and Intensity of Emissions. In ICRP Publication 38. Pergamon Press.
• Kawrakow, I. & Walters, B.R.B., 2006. Efficient photon beam dose calculations using DOSXYZnrc with BEAMnrc. Medical Physics, 33(8), p.3046.
• Klein, S., Staring, M. & Pluim, J.P.W., 2007. Evaluation of optimization methods for nonrigid medical image registration using mutual information and B-splines. IEEE transactions on image processing: a publication of the IEEE Signal Processing Society, 16(12), pp.2879-90.
• Stabin, M.G., Sparks, R.B. & Crowe, E., 2005. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. Journal of nuclear medicine: official publication, Society of Nuclear Medicine, 46(6), pp.1023-7.
• Gear, J. et al., 2011. Monte Carlo verification of polymer gel dosimetry applied to radionuclide therapy: a phantom study. Physics in Medicine and Biology, 56, p.7273.
• Eckerman, K. et al., 1994. Availability of nuclear decay data in electronic form, including beta spectra not previously published. Health physics, 67(4), pp.338-345.