Advances in Skeletal Dosimetry Through Microimaging

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


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.)


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


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


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


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


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


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


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


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)


Bone Structure

Cortical Bone• hard bone• compact bone

Cancellous Bone• spongy bone• trabecular bone

Spongiosa = trabecular bone + marrow tissues + endosteum


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


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


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


Marrow Cellularity with Age and Skeletal Site


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


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


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


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…”


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


Spiers Optical Scanning System


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


Leeds – Marrow Chord Distributions

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Chord length (microns)

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er m

icro

n) Femur Head

Femur Neck

Parietal Bone

Ribs

Iliac Crest

Cervical Vertebra

Lumbar Vertebra

Leeds - Marrow Cavities


Leeds – Bone Trabeculae Distributions

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Chord length (micron)

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freq

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er m

icro

n) Femur Head

Femur NeckParietal BoneRibsIliac CrestCervical VertebraLumbar Vertebra

Leeds - Bone Trabeculae


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


Marrow Spatial Model

70%

50%

30%

X 4


Alpha-Particles – Active MarrowComparisons to ICRP 30 and OLINDA


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


Moving Beyond CBIST in Skeletal Dosimetry


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


PIRT Model of the Lumbar Vertebra


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Abs

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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)


PIRT Model of the Proximal Femur


PIRT Model of the Pelvis


PIRT Model of the Cranium


PIRT Model of the Ribs


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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)


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%


Skeletal-Averaged Absorbed FractionsUF Model and the 2000 Eckerman Model (MIRDOSE3)

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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


Skeletal-Averaged Absorbed FractionsUF and 2003 Eckerman Model (OLINDA)

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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


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


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


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


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


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


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


95% Cellularity 60% Cellularity 15% Cellularity

PIRT ModelAdjustments for marrow cellularity


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)


PIRT ModelAdjustments for location of cellular targets

Distances From Stem Cells to Bone Trabeculae

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CD34 staining of BM biopsies

Documents

Advances in Skeletal Dosimetry Through Microimaging