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Dosimetry (DoseEstimation) ofInternalEmitters.

Lawrence E. Williams, PhD

City of Hope National Medical Center

Duarte CA 91010

lwilliams@coh.org

Outline1. DoseEstimation FormulaD = S*Ã

2. Determination of A(t)

a. six methods

b. errorsin A

3. Integration of A to form Ã

a.OpenModel

b. ClosedModel

4. Calculation of Dose

5. Errorsin Dosedueto A, Ã, andS errors.

Estimationof Doseand notDosimetry

• Dosimetry is themeasurement of absorbeddosein erg/gor Joules/kg.This isn’ t easilyor ethicallydonein living tissues.Thus,useof theterm is notappropriate in the context of radiation therapy.

• We canonly estimate theinternalemitter dose.Our limitation is similar to thatfoundin externalbeamwork. “Theydon’ t do dosimetry either”.

For Radiation Effects,is Dosetheonly Answer?

• Becauseof biologicaleffectiveness,a QF(quality factor)maybe multipliedby dose (Gray)values to yield a resultin Sieverts. Alpharay examples.

• If this is done,however,thereadermustbeshown bothvalues– not just theequivalentdose(Sv).

• Effectivedoseis not appropriatefor specific patient riskcalculationsand is intendedasa comparisonparametertousefor stochasticcalculations.

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TheGeneral Strategy of InternalEmitter DoseEstimation

Dose= S * Ã

• Where S contains thespatialefficiency of energydepositionin thetargetmass giventhesource’s emissionsand location. Ã is thetotal number of sourcedecays (timeeffects).

• Theformulais generally appliedto wholeorgansourcesand targets.It should hold downto cellular-sizedsystems.

• Space/timedichotomywill not hold if mass (t). Effectseen in lymphoma therapyat U. C. Davisand U. ofMichigan. 103 (29%)1.9d40.81Sm-153

None14 d81.70P-32

113 (6%)6.7d20.50Lu-177

155 (15%)17 h102.12Re-188

137 (9%)3.7d51.07Re-186

None2.7d112.27Y-90

360 (80%)8 days2.0mm

0.61MeVI-131

Gamma (keV)T1/2RangeBeta (MeV)Nuclide

Possible Radionuclides of Interest forInternal Emitter Therapy

UptakesAnti cipated in a MouseBiodistri bution.

If we assume100%of theinjecteddose(ID) wereuniformlydistributedin a 20 g mouse,thenormalorganor tumor“ tracerdensity” shouldbe:

100%ID/20 g = 5 % ID/g (mouse)

This is a non-targeting result.Also, we havecorrectedforradiodecayof thelabel.If we do not correct,thenumeratoris %injectedactivity (% IA). A similar resultoccurs for the adultpatient with a denominatorof 70 kg. Thecorresponding result:

1.4%ID/ kg (human)

Motivationfor InternalEmitterCancerTherapy

• Ga-67 Citrate; non-specific, 6%ID/g in mousetumor.

• Liposomes;non-specific,30%ID/g in mousetumor.

• Antibodies;specific, 60%ID/g in mouse tumor.

• PredictedHuman TumorUptake≅ 20%ID/kg.

• AbsorbedDose(α or β emitter)is proportionalto%ID/g in tumor (or tissue).

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Other Data of Interest to the FDA: Imaging Proof ofTargeting; Nude Mouse Model with LS174T HumanColon Tumor. VFC with 2µCi Co-57.

24 h 48 h 148 h

ProteinsarethePosterChildrenforTumor-Targeting Molecules.

• Specific to theTumor-associatedAntigen.

• Labeledwith DifferentRadionuclides.

• Engineeredfor MolecularWeight.

• Engineeredto beHuman-like.

• Mono or Multi-Valent.

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FDA-approvedInternal EmitterTherapies

• SIR Spheres(plastic withY-90) for Liver mets.

• Theraspheres(glasswithY-90) for Hepatoma.

Theaboveagentsrely on catheterplacementof agent.UseTc-99mMAA to definelungtoxicity.

• BexxarTositumomab(I-131)for Lymphoma.

• ZevalinIbritumomab(Y-90) for Lymphoma.

Theseagents areinjectedIV and circulate.

InternalEmitter DoseEstimation.

In orderof decreasingdifficult y theprocesshasthreesteps.

1. Most difficult: Determination of activity (A) in tissues ofinterestat varioustimes(t). Many methods.

2. Next most difficult: Integration of A(t) over very longtimes (∞) time to form Ã. Varioustechniques.

3. Leastdifficult (usually):Convertingà to dose(D) via thematrix transformation D = S * Ã. However,S mayneedto be verydifferent from OLIND A or MIRD standardphantomvalues.UseCT or MRI data.

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Two Typesof Internal EmitterAbsorbedDoseEstimatesin Patients.

• TypeI: Legal/Scientific:FDA regulationsfor PhaseITrial in patients.Here,anOLIN DA or MIRD phantom isusedfor theS factor. Ã (from animals) is adjusted to suitphantom. Uniform uptakeassumedin source.Doserefersto whole organtargets.

• TypeII : Patient-Specific:Evaluatetoxicity andtherapyinclinical trials.Thus,anatomic(CT or MRI) dataarerequired.S factor is madeto bepatient-specific, Ã is useddir ectly from thepatient.Uptake maybenon-uniform.

“TheProblem” of NuclearMedicine

• After 60 or more years, thereis still no standardtechniqueto estimateactivity (A) in apatient.Multiple methodshavebeenproposedandused,but a typical clinical studywill probablyrequireacombination of techniquesoverthe1 to 10 dayperiod allocatedto thepatientstudy.

Step1: Six Methods for Determinationof HumanActivity (A).

• Blood,SurgicalandExcreta Sampling.• ProbeImagesof Surface Lesionsor WholeBody.• Geometric Mean(GM) of Two OpposedViews.• CAMI Method.• QuantitativeSPECTfrom Fusedor Hybrid

(nuclear/CT)Scanning.• PETor PET/CTImagingwith quantitativeSUV

Results.

Methodsto Determine A arenotMutually Exclusive

In a typical clinical study,datatakerswill needtouse2 to 3 simultaneousmethodsfor measurementof A. Themost importantare:

• Blood Sampling.

• GM of wholebody(WB) images.

• QuantitativeSPECT(Hybrid Scanneror fusion).

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Direct Samplingof Blood(Tissues).

• Blood valuesneededfor bonemarrow doseestimates.

• Blood givespatient subgroup determinations.Patientsdonot fall on a Gaussiancurve.

• Blood datatakenat eachimagingtime point and severaltimes for thefirst biological half-li fe.

• Tissue samplemayprovidenormalizationof imageresults;e.g., anOR specimen.

• All arecounted with a standard from thepharmacist.

BoneMarrow DoseEstimation

• Ã (rm→ rm) = f * Ã (blood)* 1500/5000

Where f is a coefficient on theorderof 0.3andthenumeratorand denominator are RM andwholebloodmassesrespectively. This approximationneglectsspecific marrowuptakewhich mustbehandledseparatelyif present. Cf. Siegel et al Antibody Immunoconj andRadiopharm. 3 213-2331990andSgouros J.Nucl. Med.34: 689-6941993.

SingleProbeCounting

• May beusedon essential externalsitessuchasmelanoma,sarcoidor thyroid tissue.

• Attenuationcorrectioncanbesimple.

• Inversesquarelaw neededfor efficiencycorrection.

• May beusedfor wholebodyclearance.

• Countingstandardis required.

Ray 1 Ray 2

Patient outline

The Nuclear Medicine Imaging Situation

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Geometric MeanImaging

• Typically usesanterior-posterior projection.• Tissueattenuationis correctedwith CT, MRI or

direct measurement(externalsource).• Shouldhavestandard sourcein thefield of view.• Suffersfrom possibleorganand tumor overlap.• May alsosuffer from observerconfusion; hot

spotanterior image≠ hot spotposteriorimage.• Typical errorsare+/- 30 % (literature).

CAMI Method

• UsesCT data to correctattenuationalongrays ofinterestthru thepatient’s majororgansystems.

• May beusedfroma singlewholebodyscan.• Problemof activi ty becomesa setof activity

densities(kBq/cm) alongraysof interest.• Organsmayoverlap.• Problemis over-determined;least-square fitting.• Errors are+/- 10 % (literature).

Radioactivity estimation with CAMI and GM methodTwo overlapping organs (pancreas and right kidney)

Posterior(reversed)Anterior

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Radioactivity estimation with CAMI and GM methodTwo overlapping organs (pancreas and right kidney)

Total Organ Activ ities ( µµµµCi of In-111)

0

200

400

600

800

1000

1200

Pancreas RKidney LKidney LLung PartialWB RLung Spleen

Orga ns

Aci

tivi

ties

( µµ µµC

i)

CAMI

Dose Calibrator

GM Comparison

QuantitativeSPECT

• RequiresCT (MRI) anatomic datato correct forattenuation andother factors.

• Commercial systemsarebecomingavailable.• Fourstepsare idealin thealgorithm:

Attenuation.Scatter.Collimatorcorrection.Small Volumerecoverycorrection.

CommercialHybrid (SPECT/CT)Systems

• GE HawkeyeI andII• SiemensSymbia• Philips Precedence

• The partial volumecorrection is not availableonanysystemat this time.

• CT Imagesmay beinferior to stand-aloneCT.• OrganMotion betweenCT and SPECT

Severalof theResearchGroupsinvolvedin QuantitativeSPECT

• JohnsHopkins

• Lund University (Sweden)

• U of Michigan.

• U of Massachusetts

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PET/CTScanning to DetermineA

• SUV should (!) give anaccurateresult.

• No colli mator required–hencehigh effic iencycomparedto cameraandSPECT/CT.

• Yet in practice multipleSUV valuesare cited.Which oneis bestforA(t)?

• F-18 hasa 110m half life.

• I-124has100h, but only23%emissionof 511 keV

SPECT/CTResults for HawkeyeI

- 6 %- 7.5 %Average

-3, -3 %-7, -6 %Lungs(R,L)

- 14 %- 11 %Kidney

- 4 % error- 6 % errorLiver

MEGPIIMEGPOrgan

In-111 in a RSD torso Phantom with 3 JH Corrections

Step 2: Pharmacokinetic (PK)Analysis To Determine à Given A(t).

1. Open Model uses Multiple Exponential Fits toTumor, Blood and other tissues. These representeigenfunctions of the differential equations.

2. Closed Compartmental Model with connectedorgans. Blood-organ interactions are seen moreclearly in this mammilary format.

Reasonsfor PK Modeling

• Integrationof A(t), via modelparameters, to formÃ.

• Determination of kinetic variablesfor animalsandpatients.Comparing suchdata.

• Checkingfor IncorrectData.• ConvertingfromGammaEmitter(Image)Label

to the BetaEmitter (Therapy)Label.For example,goingfromIn-111-Antibodyto Y-90-Antibody.

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Blood

UrineFeces

Residual Liver

RKrb

Kbr

Kbl

Klb

Krf Klu

Kd

Kd

Kd

Kd

Kd

5 Compartment PharmacokineticHuman Data Model

Step3: Methods to DetermineAbsorbedDose(D = S*Ã)

• OLINDA, MIRDOSE3or MIRDOSE2Programs;S dependsupona given phantom.Traditional Method; favoredby regulatoryagenciesand mostusers of radioactivity.

• Voxel-BasedCalculation (MAVSK) ; S is local.

• Point-SourceKernels; S is local.

• CompleteMonteCarlo Analysis; no useof S (!).

Two Correctionsto OLINDAEstimationsof AbsorbedDose.

• Correctà (patient) to Al low Substitution intoStandardProgram.TypeI Estimate.

• CorrectS (OLINDA or MIRD) to Allow Patient-Specific Estimation of AbsorbedDose.TypeIIEstimate.

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Correction to Patient Activity for use in astandard OLINDA Dose Calculation.

Ã(MIRD) = Ã(pt) * m(MIRD)/M(MIRD)

m(pt)/M(pt)

where m is organ mass and M total body mass. Pt refers to thepatient. Here, we assume use of standard phantom S values for usein a legal/scientific context such as an FDA application. Samecorrection as used by Jeff Siegel in red marrow analysis.

Correction for Organ S values in OLINDA toCompute a Patient-Specific Absorbed Dose.

Snp (pt) = Snp (MIRD) * m(MIRD)/ m(pt)

here, m refers to organ mass and np implies non-penetratingradiation such as beta or alpha rays. We assume pt and chosenphantom have the same total mass M.

Tableof DoseCorrection ResultsA bsorbedDoseType

S Ã

I correct Changebym/M ratios

I I Changebym(MIRD)/m(pt)

correct

Example of the Useof Type I DoseEstimation.Reviewof MIRD Reports 1 through 12

Of the fi rst 12 MIRD Reports, it seemsthattwo usedanexplicitcorrection for themass of source organsandthewhole body. ThesewereReport 1 ( 75-Se-Methionine)andReport2 ( 67-GaCitrate).In bothcases,autopsydatawere available for analyses.

In thecaseof theother10 Reports,it is unclearif anycorrectionwasmadefor organmass/wholebody(m/M) massratios. Thus,theseresultsareprobablynot of TypeI.

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Errorsin Absorbed DoseEstimates.• The A valueis uncertain to +/- 30%in GM. CAMI

yields errorson theorder of +/- 10%.SPECT/CTresultsarestill beingdeveloped,but shouldbe+/-5% to +/- 10%.Staytunedfor improvements.

• Ã is +/- 10%dueto integration uncertainties.• S tablescanbeincorrect by factorsof two- or three-

fold dueto patient target organ masses.This isprobably thelargestpossible errorin theD = S* Ãformula.

Comparisonof Two RIT Protocols.

CD20+ NHL.• Zevalin c Y-90

• Tumor: Not given• Liver: 17 cGy/mCi• Spleen: 27 cGy/mCi• RedMarrow: 2.4cGy/mCi

CEA + Solid Tumors.• cT84.66c Y-90.Protocols

91064and91169.

• Tumor: 25 cGy/mCi

• Liver: 27 cGy/mCi

• RedMarrow: 3.1cGy/mCi

Normal OrganToxicity Values

?2.0 Gy?1.5 GyAcute Effects

Bonemarrow

28 (wholeorgan)

23 (wholeorgan)

Kidney

40 Gy30 GyLiver

TD 50% /5yrs

TD 5%complications/5 yrs

Organ

Emami et al Int. J. Rad. Oncol. Biol. Phys. 21: 109-122, 1991

Future Directions in Absorbed DoseEstimation.

1. Both typesof estimateswill needto bemade.Thephantomswill changeinto morehuman-appearingforms in OLINDA Thefirstkind of correction(Ã ) will continueto beused.

2. Both Typesof Estimationwill increasingly bemadewith MonteCarlocalculationsby theuser.Voxel or point sourcekernels insteadof Smatrices.This will eliminatethenecessity of the2ndkind ofcorrection (Smatrix) .

3. Dose-volumehistogramsratherthanonly meandoseswillbecomethestandardoutput of the patientcalculation.

4. A third typeof estimate,for animalsonly, wil l become ofinterestin evaluating thepre-clinical effectivenessof RIT.

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SomeReferencesfor Internal EmitterDoseEstimation

• ThePrimer.AAPM ReportNo. 71,2001.RIT.

• Stabin et al. JNM 46: 1023-1027, 2005. OLINDA.

• Siegel et al. Antibod. Immunoconj. Radiopharm. 3:213-233, 1990.BoneMarrow DoseEstimates.

• Thomaset al. Med.Phys.3: 253-255,1976. GM.

• Liu et al Med.Phys.23: 1919-1928,1996.CAMI.