advances in skeletal dosimetry through microimaging
DESCRIPTION
Advances in Skeletal Dosimetry Through Microimaging. Wesley Bolch, PhD, PE, CHP Director, Advanced Laboratory for Radiation Dosimetry Studies Department of Nuclear & Radiological Engineering University of Florida, Gainesville, FL Oak Ridge National Laboratory Tuesday, August 2 - PowerPoint PPT PresentationTRANSCRIPT
Nuclear and Radiological Engineering
Advances in Skeletal Dosimetry Through Microimaging
Wesley Bolch, PhD, PE, CHPDirector, Advanced Laboratory for Radiation Dosimetry Studies
Department of Nuclear & Radiological EngineeringUniversity of Florida, Gainesville, FL
Oak Ridge National LaboratoryOak Ridge National LaboratoryTuesday, August 2Tuesday, August 2
NCI Grant CA96441 and DOE Grant DE-FG07-02ID14327
Nuclear and Radiological Engineering
Strategies for Cancer Therapy
• External Beam Therapy (photons, protons, heavy ions)
• Insertion of Radioactive Seeds (brachytherapy)
• Radionuclide Therapy
• Unsealed Sources
• Tagged to bio-molecules (antibodies, peptides, etc.)
Nuclear and Radiological Engineering
Radionuclide TherapyUnsealed Sources
Benign Disease 131I sodium iodine Grave’s disease, goiter
32P sodium phosphate Polycythemia, thrombocythemia
90Y silicate colloid Severe arthritis
165Dy ferric hydroxideSevere arthritis
Nuclear and Radiological Engineering
Radionuclide TherapyUnsealed Sources
Malignant Disease 131I sodium iodine Thyroid cancer, residual disease
131I MIBG Metastatic neuroblastoma
111In octreotide Neuroblastoma
32P chronic phosphate Intracavity therapy
89Sr strontium chloride Painful skeletal metastases
153Sm EDTP Painful skeletal metastases
186Re HEDP Painful skeletal metastases
Nuclear and Radiological Engineering
Radioimmunotherapy (RIT)
Solid Tumors 131I anti-EGFr Recurrent gliomas
125I-425 , 131I-BC-2 Glioblastoma multiforme
131I-HMFG1, 186Re-NRLU19 Ovarian cancer
177Lu-CC49 Breast, colon, lung cancer
131I-CC49 Prostate cancer
90Y- or 131I-anti-ferritin Hepatoma
186Re HEDP Gastrointestinal cancer
90Y-ChT84.66 anti-CEA Colon cancer
Nuclear and Radiological Engineering
Radioimmunotherapy (RIT) of B-Cell Lymphoma
Non-myeloablative 131I Lym-1, LL2, Anti-B1, MB1
90Y B1, 2B8, C2B8
Myeloablative 131I B1, MB1, LL2, 1F5, BC8
90Y B1
213Bi HuM-195
Nuclear and Radiological Engineering
Fundamental Questions in RIT• What maximal radionuclide administration
can I deliver to the patient? Need to avoid normal organ complications Bone marrow, lungs, GI tract wall, kidneys
• How can I predict this maximum-tolerated activity in a given patient?
Dose-response function for marrow toxicity Perform patient-specific estimates of marrow dose
Nuclear and Radiological Engineering
MIRD Method for Calculating Internal Dose
“Integrated Activity”Integral no. of decays in source region rS
“S Value”Dose to target region rT
per decay in source rS
( ) ( )T S S T SD r r A S r r
Nuclear and Radiological Engineering
Radionuclide S Values
“Absorbed Fraction”Fraction of particle energy emitted in rS that is deposited in rT
( ) i T S i
T Si T
r rS r r
m
Nuclear and Radiological Engineering
Source and Target Regions
• Potential Sources ( rS )– Active bone marrow
• non-specific uptake (blood/fluid spaces) or specific antibody binding (cells)
– Osseous tissues of bone• Uniformly distributed within the bone volumes• Uniformly distributed on the interior bone surfaces
• Potential Targets ( rT )– Active bone marrow
• Stem cells and their precursors– Endosteum – tissue layer on the bone surfaces
• Single-cell layer containing osteoblasts (bone building cells)and osteoclasts (bone destroying cells)
Nuclear and Radiological Engineering
Bone Structure
Cortical Bone• hard bone• compact bone
Cancellous Bone• spongy bone• trabecular bone
Spongiosa = trabecular bone + marrow tissues + endosteum
Nuclear and Radiological Engineering
Tissues of the Bone Marrow
• Hematopoietic cellular component– granulocytic, erythroid, and megakaryocytic series
• Bone marrow stromal cells and extracellular matrix– adipocytes, reticulum cells, endothelial cells
• Venous sinuses and other blood vessels
• Various support cells– lymphocytes, plasma cells, mast cells, macrophages
Nuclear and Radiological Engineering
Formation of Blood CellsHemopoietic Stem Cell
(Hemocytoblast)
Lymphoid Stem Cell
BFU-Erythroid
Lymphocyte(B-, T-cells)
Prolymphocyte
Lymphoblast
Myeloid Stem Cell
Megakaryocytes
CFU-GM
Erythroid Cells
CFU-Meg
ErythrocyteRED BLOOD CELLS
CFU-Erythroid
Erythroblast
Platelets
Myeloblast
NeutrophilicMyelocyte
Monocyte(Macrophages)
Promonocyte
EosinophilicMyelocyte
Monoblasts
BasophilicMyelocyte
BasophilicBand Cell
NeutrophilicBand Cell
EosinophilicBand Cell
NeutrophilsEosinophils Basophils
Granulocytes
Leukocytes
White Blood Cells
Stromal Cells
Progenitor Cells
Blast Cells
(committed)
Mature Cells
Blood Cells
Stem Cells
Granulocytes
Leukocytes
White Blood Cells
Stromal Cells
Progenitor Cells
Blast Cells
(committed)
Mature Cells
Blood Cells
Stem Cells
Nuclear and Radiological Engineering
Marrow CellularityMarrow Cellularity = Fraction of total marrow space occupied by
hematopoietic cells (cellularity factor, CF)
≈ 1 - (Fat Fraction)
bone trabecula
active or red marrow
inactive or yellow marrow(adipocytes)
endosteum
Nuclear and Radiological Engineering
MIRD Method for Calculating Internal Dose
“Integrated Activity”Integral no. of decays in source region rS
“S Value”Dose to target region rT
per decay in source rS
( ) ( )T S S T SD r r A S r r
Nuclear and Radiological Engineering
Patient-specific estimates of
BloodRed MarrowA(t) A(t)
1RMECFF
HCT
A
(1) Direct NM imaging (2) Inference from Blood Measurements
RMECFF = red marrow extracellular fluid fraction
HCT = patient’s hematocrit
Nuclear and Radiological Engineering
Patient-specific estimates of S ?
• Out of necessity, the medical community has borrowed the ICRP reference skeletal models developed originally for radiological protection
• The ICRP model has two components…– Reference skeletal masses from the work of Mechanic (1926) – Reference absorbed fractions from the work of Spiers (early
1970s)
• Important Point – AF data come from an entirely different anatomic source than those used to define reference tissue masses
Nuclear and Radiological Engineering
Study by Mechanik (1926) as summarized by Woodward (1960)
• 6 male cadavers and 7 female cadavers (18 to 86 y)
• Senile marasmus (4 cases), tuberculosis (3 cases), heart disease (2 cases), and malaria (1 case)
• “The bodies appear to have been somewhat but not excessively, emaciated, the weights of the women ranging from 43.5 to 55.2 kg, and those of the men from 59.6 to 65.0 kg.”
• “It is most unfortunate that the bodies of previously healthy victims of accidents or other causes of sudden death were not chosen for study…”
Nuclear and Radiological Engineering
FW Spiers at the University of Leeds• Original anatomic source for current absorbed
fractions• Single 44-year-old male (skeletal reference man)• Contact radiographs taken
– Parietal bone, cervical vertebra, lumbar vertebra, rib, iliac crest, femur head, and femur neck
• Optical scanning system developed• Chord length distributions were obtained
– Marrow cavities– Bone trabeculae
Nuclear and Radiological Engineering
Current Models of Skeletal Dosimetry• 1D models of
particle transport
• Only 7 skeletal sites
• Single 44y male
• Masses of target tissues taken for other studies
Nuclear and Radiological Engineering
Leeds – Marrow Chord Distributions
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
0.0012
0 500 1000 1500 2000 2500 3000 3500 4000
Chord length (microns)
Nor
mal
ized
freq
uenc
y (p
er m
icro
n) Femur Head
Femur Neck
Parietal Bone
Ribs
Iliac Crest
Cervical Vertebra
Lumbar Vertebra
Leeds - Marrow Cavities
Nuclear and Radiological Engineering
Leeds – Bone Trabeculae Distributions
0.0000
0.0005
0.0010
0.0015
0.0020
0.0025
0.0030
0.0035
0.0040
0.0045
0.0050
0 100 200 300 400 500 600 700 800 900 1000
Chord length (micron)
Nor
mal
ized
freq
uenc
y (p
er m
icro
n) Femur Head
Femur NeckParietal BoneRibsIliac CrestCervical VertebraLumbar Vertebra
Leeds - Bone Trabeculae
Nuclear and Radiological Engineering
Applications for and particles
CBIST modeling approach• Chord-Based Infinite Spongiosa Transport• Both and particles are following through an
infinite expanse of spongiosa (interior tissues of trabecular bone) until their full emission energy is expended
• No accounting for electron escape to cortical bone
Nuclear and Radiological Engineering
Alpha-Particles – Active MarrowComparisons to ICRP 30 and OLINDA
Nuclear and Radiological Engineering
Applications for photons• Absorbed dose to active bone marrow
– Fluence-to-dose response function (DRF)• Based upon CBIST electron results
– Mass energy absorption coefficient (MEAC) ratio– CT number method
• Provides for a unique composition per skeletal voxel
• Absorbed dose to endosteum– Fluence-to-dose response function (DRF)
• Based upon CBIST electron results – Homogeneous bone dose approximation
Nuclear and Radiological Engineering
3D Image-Based Skeletal Dosimetry UF Adult Male Model
• Cadaver selection (66 yr, 68 kg, 173 cm, 22.7 kg m-2)
• Whole-body CT imaging (~ 1 mm3 voxels)
• Bone site harvesting (13 major sites of adult active bone marrow)
• Ex-vivo CT imaging of each excised skeletal siteImage processing → volumes of spongiosa (1 mm x 0.3 mm2)Spongiosa → combined tissues of trabeculae, endosteum,
active and inactive marrow
• Section skeletal sites – cubes of spongiosa• Microimaging of spongiosa
NMR microscopy or CT (30 – 80 m3)
• Radiation transport simulation of electron/betas
Nuclear and Radiological Engineering
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0.9
1.0
0.01 0.1 1 10Electron energy (MeV)
Abs
orbe
d fr
actio
n to
TA
M
Infinite spongiosa (TAM)Infinite spongiosa (TBV)Infinite spongiosa (TBS)Paired image (TAM)Paired image (TBV)Paired image (TBS)
TAM source
TBS source
TBV source
L4 vertebra - 70% marrow cellularity
PIRT Model of the Lumbar Vertebra (70% cellularity)
Nuclear and Radiological Engineering
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M
Infinite Spongiosa (TAM)Infinite Spongiosa (TBV)Infinite Spongiosa (TBS)Paired Image (TAM)Paired Image (TBV)Paired Image (TBS)
Rib Cage (Left) -70% Marrow Cellularity
TAM source
TBS source
TBV source
PIRT Model of the Ribs (70% cellularity)
Nuclear and Radiological Engineering
ICRP and UF Active Marrow Masses by Skeletal Site
x x x xTAM TAMUF -RM UF -RM UF -RM Variablem = SV MVF CF ρ
ICRP 89 Reference Male UF Adult Male ModelMarrow TAM Mass TAM mass TAM Mass TAM mass
Skeletal Site Cellularity (g) (%) (g) (%)
Cranium 38% 88.9 7.6% 24.4 2.5%Mandible 38% 9.4 0.8% 5.2 0.5%Scapulae 38% 32.8 2.8% 31.5 3.3%Clavicles 33% 9.4 0.8% 7.3 0.8%Sternum 70% 36.3 3.1% 19.6 2.0%Ribs 70% 188.4 16.1% 117.1 12.1%Cervical Vertebra 70% 45.6 3.9% 32.1 3.3%Thoracic Vertebra 70% 188.4 16.1% 172.8 17.9%Lumbar Verebra 70% 143.9 12.3% 131.3 13.6%Sacrum 70% 115.8 9.9% 87.0 9.0%Os Coxae 48% 204.8 17.5% 222.0 23.0%Proximal Femur 25% 78.4 6.7% 82.9 8.6%Proximal Humerus 25% 26.9 2.3% 32.42 3.4%
Totals 1170 99.9% 966 100%
Nuclear and Radiological Engineering
Skeletal-Averaged Absorbed FractionsUF Model and the 2000 Eckerman Model (MIRDOSE3)
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d fr
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TA
M
Eckerman 2000 (TAM)Eckerman 2000 (TBV)Eckerman 2000 (TBS)UF (TAM)UF (TBV)UF (TBS)UF (CBV)
TAM source
TBS source
TBV source CBV source
Discrepancy:Uniform scaling vsexplicit modelingof marrow cellularity
Discrepancy:Energy loss to cortical bone is or is notconsidered in the model
Discrepancy:Trabecular endosteum is eitherinclusive or exclusive of the active bone marrow
Skeletal Averaged Absorbed Fractionsat Reference Cellularities
Nuclear and Radiological Engineering
Skeletal-Averaged Absorbed FractionsUF and 2003 Eckerman Model (OLINDA)
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d fr
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n to
TA
M
Stabin 2003 (TAM)Stabin 2003 (TBV)Stabin 2003 (TBS)UF (TAM)UF (TBV)UF (TBS)UF (CBV)TAM source
TBS source
TBV source
Skeletal Averaged Absorbed Fractionsat Reference Cellularities
CBV source
Nuclear and Radiological Engineering
How can one adjust this image-based skeletal model to the individual patient?
• Factors to consider… – Physical stature (size of the skeleton)
• Decreases in physical stature will result in higher electron escape to cortical bone
– Bone mineral status• Decreases in BMD are primarly associated with thinning
and eventual loss of bone trabeculae. Loss of bone mass is usually accompanied by increases marrow fat (MVF x CF perhaps remains constant)
– Marrow cellularity• Changes in marrow cellularity can be accounted for
explicitly in the PIRT or other image-based models
Nuclear and Radiological Engineering
Clincial Input Data for patient-specific model adjustment
• Pelvic SPECT-CT of RIT Patient – SPECT image
• quantify marrow / skeletal uptake in sacrum or lumbar vertebrae
– CT image• Make skeletal size measurement (e.g., pelvic height)
– CT image• Using a calibration curve from a previously imaged BMD
phantom, assess the patient’s volumetric BMD (femoral neck, lumbar vertebrae)
• MR imaging or BM biopsy• Assess marrow cellularity of the patient,• Assume reference values or some proportional change
thereof
Nuclear and Radiological Engineering
PIRT ModelAdjustments for skeletal stature
( )2,A IBP1 2 1Total Spongiosa Volume( SV) ≈ f AP , P ,IBPFrom previous cadaver skeletal studies…
where AP – anthropometric parameter such as total body height or head circumference
IBP – image-based parameter such as pelvic height PIRT model run at size specific to the patient
Nuclear and Radiological Engineering
PIRT ModelAdjustments for skeletal stature
Lumbar Vertebra - L2 microstructure AF(TAM < TAM) at 70% Reference Cellularity
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Max subject (Radius 2.5, Height 3.1)66yr subject (Radius 2.2, Height 2.7)Min subject (Radius 2.0, Height 1.7)
VBIST Results
Nuclear and Radiological Engineering
PIRT ModelAdjustments for bone mineral status
( )2 1 2, , ,M A IBP BMD BMD1 2 1Total arrow Volume ≈ f AP , P ,IBPFrom previous cadaver skeletal studies…
where BMD – volumetric CT-based bone mineral density measured at the femoral head/neck and lumbar vertebrae
PIRT model run using microCT images from a reference library
Normal BMDv CT Images
Osteopenic BMDv CT Images
Osteoporotic BMDv CT Images
Nuclear and Radiological Engineering
PIRT ModelAdjustments for bone mineral status
Lumbar Vertebra - L3 microstructure AF(TAM < TAM) at 100% Reference Cellularity
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Leeds 25y Male
Leeds 44y Male
Leeds 55y Female
Leeds 85y Female
UF 66y Male
Nuclear and Radiological Engineering
95% Cellularity 60% Cellularity 15% Cellularity
PIRT ModelAdjustments for marrow cellularity
Nuclear and Radiological Engineering
Scalability of Image-Based ModelsImproved Patient Specificity
UFSacrumPatie
UFS nt
Sacruacrum
m
MVFMVF
≈ S TAM ←TAM
UFSacru
UF UFPatient UF Sacrum SacrumSacrum Sacrum Patien
m TAMPatit ent
Sacrum TAMPatient
Sacrum Sacrum
SV MVFS TAM ←TAM ≈ S TAM ←TAM
SV M CVFCF ρ
F ρ
UFUF SacrumSa
UFSacrumPatient
Scrum Patient
Sacrurum mac
SVS
MVF≈ S TAM ←TAM
FV MV
biopsy or MR imaging(Ballon et al. MP 1996)
CT measurements in patientat a reference skeletal site (e.g., LV or sacrum)(Shen et al. JNM 2002)
BMDV measurementat same skeletal site (e.g., LV or sacrum)