Relatively low administered activities yield important diagnostic information, the benefits of which far outweigh anypotential risk associated with the attendant normal-tissueradiation doses. Such small risk-to-benefit ratios have beenvery forgiving of possible inaccuracies in dose estimates.

By incorporation of radionuclides in appropriately largeamounts into target tissue—avidradiopha.rmaceuticals, asufficiently high radiation dose may be delivered to producea therapeutic response in tumor or other target tissue. Withescalating administered activities and associated normaltissue doses, serious radiation injury can ensue, however. Itbecomes imperative, then, that the magnitude of the targettissue and at-risk normal tissue radiation doses be established with reasonable accuracy and precision and used inconjunction with reliable dose—responserelationships fortarget tissues and dose—toxicity relationships for normaltissues. With the ongoing development of new radiopharmaceuticals and the increasing therapeutic application of internal radionuclides (particularly in the form of radioimmunotherapy), radiation dosimetry in nuclear medicine continuesto evolve from population- and organ-average to patientand position-specific dose estimation (1—3).Patient-specificdosimetry refers to the estimation of radiation dose to tissuesof a specific patient, based on his or her individual bodyhabitus and measured radiopharmaceutical kinetics ratherthan on an average anthropomorphic model and hypothetickinetics. In contrast to the average dose, position-specificdosimetry refers to radiation doses to specific points in atumor or organ and thus reflects the spatial variation in dosewithin a target tissue. This article reviews the historicalmethods and newly developed concepts and techniques tocharacterize radionuclide radiation doses.

STOCHASMAND DETERMINISM

Dosimetric quantities may be characterized as stochasticor deterministic (i.e., nonstochastic). A quantity subject tostatistical fluctuations because of the small number ofenergy deposition events contributing to the quantity or thesmall volume of the region for which the quantity is beingdetermined is termed “stochastic.―The mean, or expectation value, of a large number of determinations of a

Internal dosimetry deals with the determination of the amountand the spatial and temporal distribution of radiation energydeposited in tissue by radionuclides within the body. Nuclearmedicine has been largely a diagnostic specialty, and modelderived average organ dose estimates for risk assessment,thetraditionalapplicationof the MIRDschema,have provenentirelyadequate. However,to the extent that specific patients deviatekinetically and anatomically from the model used, such doseestimates will be inaccurate. With the increasing therapeuticapplication of internal radionuclides and the need for greateraccuracy, radiation dosimetry in nuclear medicine is evolvingfrom population- and organ-average to patient- and positionspecific dose estimation. Beginningwith the relevant quantitiesand units, this article reviews the historicalmethods and newlydevelopedconceptsand techniquesto characterizeradionuclideradiationdoses. The latter include the 3 principalapproachestothe calculation of macroscopic nonuniform dose distributions:dose point-kernelconvolution,MonteCarlosimulation,andvoxelS factors. Radiationdosimetry in “sensitive―populations,including pregnantwomen, nursingmothers,and children,also will bereviewed.

KeyWords:dosimetry;MIRD;radionuclidetherapyJ NucIMed2000;41:297—308

ntemal radionuclide radiation dosimetry deals with thedetermination of the amount and spatial and temporaldistribution of radiation energy deposited in tissue byradionuclides within the body. Internal dosimetry has beenapplied to the determination of tissue doses and relatedquantities for occupational exposures in radiation protection,environmental exposures in radiation epidemiology, anddiagnostic and therapeutic exposures in nuclear medicine.Historically, nuclear medicine has been largely a diagnosticspecialty, and the associated risk—benefitanalyses implicitlyperformed by the clinician have been straightforward.

Received Sep. 20, 1999; revision accepted Oct. 12, 1999.For correspondenceor reprintscontact:Pat B. Zanzonico,PhD, Nuclear

MedicineService,MemorialSloan-KetteringcancerCenter,1275YorkAve.,NewYork, NY 10021.

*NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ARTICLE ON THESNMWEBSITE(httpJ/www.snm.org)UNTILAUGUST2000.

RADIATION Dosmtirn@y •Zanzonico 297

Internal Radionuclide Radiation Dosimetry:A Review of Basic Concepts and RecentDevelopments *Pat B . Zanzonico

Nuclear Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York

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stochastic quantity is termed “deterministic.―Each stochastic quantity thus has a corresponding, generally morefamiliar, deterministic quantity.

The field of microdosimetry deals with the number, size,and spatial and temporal distributions of individual energydeposition events, particularly in submicroscopic structures(4—6).Increasingly, radiation dosimetry in nuclear medicinedeals with the nonuniformity of dose within organs, amongcells, and even within cells. Even so, dose is still almostalways expressed in terms of deterministic quantities, andsuch dosimetry should therefore not be referred to asmicrodosimetry. Terms such as “small-scaledosimetry― or“cell-leveldosimetry― would be more appropriate. However, the nonuniformity of energy deposition associated witha-ray emitters (7,8) and with radioimmunotherapy (9) maywarrant the rigorous application of microdosimetry (10).

RADIATIONQUANTiTiESAND UNITS

Definitions of various quantities used to specify radiationdose and of selected related quantities are presented here. Acompilation of System Internationale (SI) and conventionalquantities and their symbols, units, and conversion factorsare presented elsewhere (6,11).

Administered ActivftyAdministered activity is specified by the SI unit bec

querel, equaling 1 disintegration/s (dps) or some multiplethereof. The conventional unit of activity, the Curie, corresponds to 3 X l0@@dps. Note that 37 MBq equals 1 mCi and37 kBq equals 1 MCi. It is important to distinguish theradiation dose from the administered activity, with theformer quantity taking into account the radionuclide and itsphysical characteristics, tissue mass, and the radiopharmaceutical and its kinetics as well as the administered activity.

Absorbed Dose and Specific EnergyPerhaps the most widely used and biologically meaning

ful quantity for expressing radiation dose, the absorbed dose(D), is defined as:

dEDan—,

dm

where d@ = the mean energy imparted by ionizing radiationto matter and dm = the mass of matter to which the energy isimparted.

The absorbed dose, defined for all ionizing radiations inany stopping medium, is the deterministic correlate of thestochastic quantity, specific energy (z1):

€1

z1 m

unit is the rad (1 rad 100 erg/g); 1 Gy equals 100 rad, and1 rad equals 1 cGy (or 10 mGy) (11).

LinearEnergyTransferandLinealEnergyThe quality and the quantity of radiation are important

determinants of the frequency or severity of radiogenicbiologic effects. The quality of a radiation is related to thecharacteristics of the microscopic spatial distribution ofenergy-deposition events. Sparsely ionizing radiations, suchas x- and ‘y-raysand intermediate- to high-energy electronsand @3-rays,are characterized as low-quality radiations.Densely ionizing radiations, such as low-energy electrons(e.g., Auger electrons), protons, neutrons, and a-rays, aretypically characterized as high-quality radiations. For thesame absorbed dose, the frequency or severity of biologiceffects is generally less for sparsely ionizing than for denselyionizing radiations.

The quality of radiation is characterized by the linearenergy transfer (L or LET):

dELank, Eq.3

where dE = the energy lost by a charged particle (or thesecondary charged particle produced by the primary radiation) in traversing a distance in matter and dl = the distancetraversed in matter.

LET is the deterministic correlate of the stochasticquantity, lineal energy (y):

€1yan--,

Eq.2

where €@= the energy imparted to matter by a singleenergy-deposition event and m = the mass of the matter.

The unit of absorbed dose and specific energy is the same:the SI unit is the gray (1 Gy = 1 J/kg), and the conventional

Eq. 4

where €1= the energy imparted to matter by a singleenergy-deposition event and 1 = the mean chord length ofthe volume of matter.

The unit of linear energy transfer and lineal energy is thesame: the SI unit is the J/m and the conventional unit is thekeV4tm; 1 J/m equals 6.25 X 10@keV/j.im, and 1 keV/@.imequals 1.60 x l0@°J/m(11).

RelativeBiologicEffectivenessEq. 1 The influence of LET on the frequency or severity of

biologic effects is quantified by the relative biologic effectiveness(RBE):

RBE(A) an DrricrenceEq.5

where Dref@n@= the absorbed dose of reference radiation(typically a widely available, sparsely ionizing radiation,such as cobalt-60 “1'-rays)required to produce a specific,quantitatively expressed biologic effect and DA = theabsorbed dose of radiation A required to produce the samefrequency or severity of the same specific biologic effect,with all pertinent parameters maintained as nearly identicalas possible. The RBE is a ratio of absorbed doses and thus isa dimensionless quantity.

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Typeandenergyrange

1

RadiationWeightingFactorandEquivalentDoseA simplified version of the RBE, the radiation weighting

factor (wR), was devised for purposes of radiation protection(Table 1). The so-called equivalent dose (HT) in tissue ororgan T is related to the radiation weighting factors (w@Jandthe mean absorbed doses (D,@.,R)to tissue or organ T fromradiations (R):

HT@ wRDTJ@.

The wR and H1 are similar, respectively, to the olderquantities of quality factor (Q) and dose equivalent (H). Thekey difference is that the former are related to the mean doseto a tissue or organ, whereas the latter are related to the doseat a point and thus are often less useful.

Tissue Weighting Factor and Effective DoseThe effective dose (E) is intended to provide a single

value estimate of the overall stochastic risk (i.e., the totalrisk of cancer and genetic defects) of a given irradiation,whether received by the whole body, part of the body, or 1 ormore individual organs:

Ean@wTHT Eq.7

=@@ wTwRDT,R,

where wT the weighting factor for tissue or organ T, adimensionless quantity representing the fraction contributedby tissue or organ T to the total stochastic risk (i.e., thecombined total risks of cancer or of severe hereditary defectsfor all subsequent generations) as the result of a uniform,

total-body irradiation (Table 2). The effective dose is similarin concept to the effective dose equivalent (HE) introducedpreviously by the International Commission on RadiationUnits and Measurements (12) and the National Council onRadiation Protection (13) and representing a single-valueestimate of the net harm from any low-dose (e.g., diagnosticnuclear medicine) exposure. However, the dose equivalent is

Eq 6 based on the absorbed dose at a point in tissue weighted bythe LET-dependent distribution of quality factors at thatpoint. The equivalent dose, in contrast, is based on theaverage absorbed doses in the tissue or organ weighted bythe radiation weighting factor for the radiation actuallyimpinging on that tissue or organ. The effective dose and theeffective dose equivalent do not apply to, and should not beused for, high-dose (e.g., therapeutic nuclear medicine)exposures (14).

The unit of equivalent dose and effective dose is the same:the SI unit is the sievert and the conventional unit is the rem;1 Sv equals 100 rem, and 1 rem equals 1 cSv (or 10 mSv)(13). wR and w1 are dimensionless quantities (Tables 1 and2) (15,16).

Eq. 8 The methodology now widely used used for internal dosecalculations in medicine, including age- and sex-specificreference data for human anatomy and body composition,was developed by the MIRD committee of the Society ofNuclear Medicine and is generally referred to as the MIRDschema or MIRD formalism (2,17—19).The InternationalCommission on Radiological Protection (ICRP) has develo_ a similar methodology and similar reference data (20).

The MIRD schema, including notation, terminology,mathematic methodology, and reference data, has beendisseminated in the form of the collected MIRD pamphletsand associated publications (2, 17—19).With the publicationof work by Christy and Eckerman (21), age- and sex-specificbody habiti other than the original 70-kg adult anthropomorphic model (known as “StandardMan―)(22) now areincorporated into the MIRD schema. In addition, severalcomputerized versions of the MIRD schema have been

5 developed, including MIRDOSE (23), DOSCAL (which20 incorporates mean tumor doses) (24), and MABDOS (with

curve fitting and modeling features) (25—27).In its traditional application to diagnostic radiopharmaceu

ticals, the MIRD schema implicitly assumes that activity andcumulated activity are uniformly distributed within organsize source regions and that radiation energy is uniformlydeposited within organ size target regions. Moreover, dosimetry for diagnostic radiopharmaceuticals is generally basedon (a) average time—activitydata in animal models or insmall cohorts of human subjects and (b) age- and sexspecific “average―models of human anatomy. The traditional MIRD schema does not incorporate tumors as eithersource or target regions.

5102010

THE TRADITiONALMIRDSCHEMA

TABLEIWR for Calculation of HT to Tissue or Organ

xandy-rays,electrons,positrons,andmuons*Neutrons,energy

<10 keV10-100 keV>100 keV-2 MeV>2-20 MeV>20 MeV

Protonstotherthanrecoilprotonsandenergy> 2 MeVa particles, fission fragments, nonrelativistic heavy nuclei

*ExcludingAuger electronsemittedfrom nucleiboundto DNA,becauseaveragingdose in this case is unrealistic.Techniquesofmicrodosimetryare moreappropriateinthiscase.

tIn circumstancesin whichhumanbody is irradiateddirectlyby>100-MeVprotons,RBEis likelyto be similarto that of low—linearenergytransferradiation,and, therefore,wRof approximatelyunitywouldbe appropriateforthatcase.

1@VRvalue for high-energy protons recommended here is lowerthan that recommendedby InternationalCommissionon RadiologicalProtection(1991).

All values relate to radiationincidenton body or, for internalsources,emittedfromsource.Adaptedwithpermissionof(16).

RADIATION DOSIMETRY •Zanzonico 299

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wT Tissue or organ

TABLE2WT for Tissue or Organ for Calculation of Effective Dose

source and target regions, it can be used to calculate the doseto virtually any structure from virtually any activity distribution, from microscopic to macroscopic to whole organ andwhole body. With the publication of MIRD Cellular SFactors (28), the MIRD schema has been extended tocellular and subcellular source and target regions, with thecell and the nucleus modeled as unit density concentricspheres of radius 3—10and 1—8pm, respectively. Morerecently, MIRD pamphlet no. 17, The Dosimetry of Nonuniform Activity Distributions: Radionuclide S Values at the

VoxelLevel(29) has extended the MIRD schema to arbitrary

macroscopic activity distributions in 3 dimensions forcalculation of the resulting macroscopic dose distribution. Inthis context, macroscopic refers to volume elements (orvoxels) 3 mm or greater in dimension. In both publications,the distance-dependent photon and electron dose contributions are included and, in the case of @3-rays,the actualenergy spectra (versus simply the mean energy) are used.

Patient-SpecificDosimetryIndividual variations in radiopharmaceutical kinetics may

result in substantial deviations from population-averagedose estimates, so that they are not predictive of target tissueresponse or normal tissue toxicity in radionuclide therapy.This is illustrated by the various dosimetric approaches toradioiodine treatment of hyperthyroidism (30).

The clinical effectiveness of radioiodine treatment ofhyperthyroidism is presumably related to the absorbed doseto thyroid follicular cells. Yet, the most common doseprescription algorithm, a fixed administered activity, entailsadministration of a specified activity (currently, approximately 370 MBq [10 mCi]) to all hyperthyroid patients. Byignoring those highly variable individual parameters (i.e.,thyroid uptake, biologic half-life, and mass) that determineabsorbed dose, it is unlikely that there will be a correlationbetween the administered activity and the absorbed dose(Fig. 1). Although up to 85% of patients will eventually be“cured―(i.e., made euthyroid or hypothyroid) by theadministration of single doses of standard amounts ofradioiodine (and presumably 100% of patients treated withrepeated administrations) (31), such an arbitrary approachdoes not permit individually optimized therapy and wouldnot identify patients such as “small-pool―patients for whomradioiodine therapy may be inappropriate or even hazardous.

Prescription of a specified activity concentration (typically 2000—3000 MBq/g [55—80pCi/g]) in the thyroidincorporates 2 important dosimetric variables, thyroid uptake and mass, into calculation of the administered activitybut implicitly assumes a constant thyroid half-life of radioiodine:

administered activity =

prescribed activity concentrationx glandmass(g) X 100

24-h % uptake

A prescribed absorbed dose (Gy [rad]) is the dose

0.010.050.120.20

Bonesurface,skinBladder,breast,liver,esophagus,thyroid,remainder*Bonemarrow,colon,lung,stomachGonads

*For purposes of calculation, remainder is composedof thefollowingadditionaltissuesand organs:adrenals,brain,smallintestine, large intestine,kidney,muscle,pancreas,spleen,thymus,anduterus.Listincludesorgansthatare likelytobe selectivelyirradiated.Someorgansin listare knownto be susceptibleto cancerinduction.Ifothertissuesandorganssubsequentlybecomeidentifiedas havingsignificantriskof inducedcancer,they will then be includedeitherwith a specificw, or in this additionallist constitutingremainder.Remaindermay also includeother tissues or organs selectivelyirradiated.In thoseexceptionalcases inwhich1 remaindertissueororganreceivesequivalentdose in excessof highestdosein any ofthe 12organsforwhichweightingfactorisspecified,weightingfactorof0.025 shouldbeappliedtothattissueororganandweightingfactorof0.025 toaveragedoseinotherremaindertissuesororgans.

Valueshave been developedfor referencepopulationof equalnumbersof both sexes and wide range of ages. In definitionofeffectivedose, they apply to workers,to whole population,and toeithersex.ThesewTvaluesarebasedon roundedvaluesof organ'scontributionto totaldetrimentAdaptedwithpermissionof(16).

BEYONDTHE TRADITIONALMIRDSCHEMA

The traditional MIRD schema has proven invaluable fordosimetric risk assessment in diagnostic nuclear medicine.However, to the extent that specific patients deviate kinetically and anatomically from the respective kinetic andanatomic averages, tissue dose estimates will be inaccurate.Robert Loevinger, an originator of the MIRD schema, hasstated that, “.. .there is in principle no way of attaching anumerical uncertainty to the profound mismatch betweenthe patient and the model (the totality of all assumptions thatenter into the dose calculation). The extent to which themodel represents in some meaningful way a patient, or aclass of patients, is always open to question, and it is theresponsibility of the clinician to make that judgment―(19).Because of the large risk—benefitratios associated withdiagnostic radiopharmaceuticals, any inaccuracies (perhapsup to 100% [2]) in tissue absorbed dose estimates forindividual patients probably are unimportant. With therapeutic radiopharmaceuticals, however, the risk-benefit ratios aredramatically smaller, and the tolerances for inaccuracies indose estimation are greatly reduced.

With the growth of radionuclide therapy, various techniques beyond the traditional MIRD schema have beendeveloped to improve the accuracy of dose estimates,including techniques for patient- and position-specific radiation dosimetry. Any perception that such techniques somehow correct inherent limitations of the MIRD schema ismistaken, however. Indeed, a remarkable strength of theMIRD schema is its generality: by judicious selection of

.Eq.9

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100

Ia

FIGURE1. Relativeerrorin calculated‘31labsorbeddoseto thyroidasfunctionofrelative error in thyroid 24-h uptake, biologic half-life, and mass. Baseline parameters are 24-h uptake of 25%, biologichalf-lifeof9Od, and massof2l g. Notethat,for errors in biologic half-life, relative errorinthyroidabsorbeddosebecomesimportant only for very large negativeerrors. Forexample,if actual biologichalf-lifewereonly 5 d (typical of small pool patients),actualthyroiddosewouldbe overestimatedby—60%if oneassumesstandardbiologichalf-lifeof90 d.

-60

-80

-100

S Errer In Pamms@r

(T1,@)@X (Tl,@)b

(T1,@)@+ (Tl,@)b'

prescription algorithm presently used least often, because itulation.) Because the 1311@y-raystypically contribute<10%requiresserial uptake measurements and is therefore timeof the dose, deviations of thyroid masses from theassumedconsuming.

However, it is the most logical dosimetrically,value of 25 g have only a minor effect on the thyroiddoseincorporatingall pertinent and practically evaluable param calculated using Equation9.eters

into the calculation of the administered activity:The following have been offered as general guidelinesfor.. . .

administered activity (kBq) =single-doseradioiodine therapy of hyperthyroidism (35,36):

. .

for young patients and those with uncomplicatedGravesprescribedabsorbed dose (cGy)disease (i.e., small glands and mild to moderate hyperthyroid

x glandmass(g) X 6.67 x 37

(Tl@)eff(day) X 24-h % uptake ‘@ 10ism),

7,000—8,000rad; for patients with complicated Graves'disease (i.e., larger glands and more severe hyperthyroidism), 10,000—12,000rad; and for patients with toxicnodularwhere

(T1@)eff= the effective half-life of radioiodine in thegoiter, 15,000—25,000 rad. However, in contrast totypicalthyroid,which in turn equalshyperthyroid patients ([T1,@}b= 20—25d), 15% of hyperthy

roid patients have a more rapid thyroidal turnoverofEq.11radioiodine ([Tl,@]b= 5—10d). This is thought to be the result

of a small thyroidal iodine pool (small-pool syndrome). Asawhere

(Tl,@)b the biologic (or radioactive decay-corrected)result, serum protein-bound radioiodine, the source ofashalf-lifeof radioiodine in the thyroid, and (T1,@)@= themuch as 90% of the 1311blood absorbed dose, is elevated(tophysicalhalf-life of ‘@‘I(8.04 d). Implicit in Equation 10 areas high as 2% of the administered activity per liter ofserum),the

assumptions that the only significant absorbed dose towith a resulting increase in the blood absorbed dose. Atthethethyroid is from self-irradiation, all nonpenetrating radia same time, the thyroid absorbed dose is reducedbecausetions

(i.e., @3-rays)emitted within the thyroid are completelyradioiodine is more rapidly secreted from, and thereforehasabsorbed

locally, and the proportion ofthyroid mass attribut less time to irradiate, the thyroid. The relativelysmallableto lymphocytes is negligible. The factor of 6.67 wasthyroidal absorbed dose in small-pool patients isprobablyderived

by Marmnelli et al. (32—34)(a) assuming the thyroidresponsible for at least some failures of radioiodine treatto have a mass of 25 g and to consist of 2 unit density tangentment. Barandes et al. (37), for example, reported a series of7spheres,

each of mass 12.5 g and radius (R) of 1.44 cm,small-pool hyperthyroid patients in whom a standard7000-yieldinga mean geometric factor (gsp,@re)3 1TR of 12.3 cm;cGy (7000-md) thyroid absorbed dose would requirethe(b)

assuming radioiodine in the thyroid follows a monoexpo administration of 1040 MBq (28 mCi) 1311(in contrasttonentialtime—activity function; (c) using a mean @3-rayonly 120 MBq (3.2 mCi) typically required) and theoreti

energy of 0.191 MeV and a specific rny-rayconstant ofcally deliver a blood absorbed dose of 150 cGy (150 rad),a0.00223R cm2/mCi/h (in conventional units) for 1311;and (d)prohibitively high incidental dose for treatment of abenignincorporating

the appropriate unit conversion factors.(Thedisease.factorfor converting pCi to kBq, 37, is presented explicitlyA general patient-specific treatment-planning paradigmisto

retain the familiar factor of 6.67 in the Marineffi form as follows (30,38—42).A tracer (diagnostic) amount of the

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therapeutic radiopharmaceutical is administered to the patient. Serial time—activity measurements are performed forblood, tumor, or other target tissue; critical normal organs; orthe total body (30,41,43,44). These kinetic data are integrated to determine the corresponding cumulated activities(or residence times), and the absorbed doses per unitadministered activity are calculated. The actual therapeuticadministered activity is that projected to deliver maximumtolerated doses to 1 or more critical normal tissues or, lesscommonly, a minimum effective dose to tumor or othertarget tissue. For ‘31I-iodidetreatment of metastatic thyroidcancer, for example, the therapeutic administered activity isthat calculated to deliver no more than 2 Gy (200 rad) toblood (as a surrogate for bone marrow) (30,41,45,46). Inradioimmunotherapy of non-Hodgkin's B-cell lymphomawith 1311-labeledanti-B! (anti-CD2O) monoclonal antibody,on the other hand, the therapeutic administered activity isthat delivering a dose of 0.75 Gy (75 rad) to the total body(again as a surrogate for bone marrow) (47—50). Forradiolabeled monoclonal antibody and other targeted therapies in which uptake is saturable or otherwise nonlinear,with varying “mole―amounts administered, mathematic(e.g., compartmental) modeling of the tracer kinetic datamay be useful in determining the optimum amount (mole ormg) as well as activity of the therapeutic radiopharmaceutical (51—57). After the therapeutic administration, serialtime—activity measurements and cumulated-activity andabsorbed-dose calculations may be repeated and the projected and actual therapeutic absorbed doses compared.

NonuniformDoseDistributionsNormal tissue toxicity and tumor therapeutic response

may not correlate with average doses, even when based onindividualized kinetics. Thus, in addition to patient-specificdosimetry, the issue of spatial nonuniformity of dose hasbecome increasingly important at the macroscopic (29,58—77) and microscopic (78—96)levels.

FIGURE2. Nonuniformityof bonemarrowabsorbeddose.Absorbeddoseperunitadministered activity (mGy/MBq) to bonemarrowinfemoralheads(FernHead),humeralheads(HumHead),andlumbarvertebrae 3 and 4 (L3+L4) was evaluatedin 9patients with leukemia who received 300MBq131l-labeledHuM195anti-CD33monoclonalantibody.Note2- to3-foldvariationinestimated absorbed doses among 3 marrow sites. (Adapted with permissionof(131).)

Potential radiogenic damage to the hematopoietic bonemarrow is the primary dose-limiting toxicity for systemicradionuclide therapy in general and radioimmunotherapy inparticular (45,97,98). A variety ofapproaches have thereforebeen pursued in an effort to establish a predictive doseresponse relationship for myelotoxicity in radioimmunotherapy (97,99—101). Although no such correlation hasproven especially useful (50,102—107),absorbed dose yieldsa better correlation than administered activity. Moreover,marrow absorbed dose appears to be a marginally betterpredictor of myelotoxicity than whole-body absorbed dose.However, in an intermediate absorbed-dose range, myelotoxicity has been unpredictable. This may be a notable exampleof the inadequacy of the average dose as a quantitativedescriptor of tissue irradiation and potential toxicity (Fig. 2).

Nonuniformity of dose in target tissues such as tumorlikewise may make it difficult to reliably predict therapeuticresponse in radionuclide therapy. O'Donoghue (108) hasmodeled the impact ofdose nonuniformity (109) on radiocurability of tumors. As shown in Figure 3, tumor response ispoorer (i.e., tumor cell survival is greater) as dose nonuniformity increases. The dose—response curve is concave upward(Fig. 3D), indicating that the tumor-sparing effect of dosenonuniformity is greatest at higher doses. A substantialfraction of tumor cells will therefore receive sublethal doses,and the tumor may therefore not regress, even if the averagetumor dose is sufficiently high to otherwise create anexpectation of a significant therapeutic response. A clinicallypredictive average dose—responsecurve may be difficult orimpossible to derive in the face of such nonuniformity.

There are at least 3 approaches to the calculation ofmacroscopic nonuniform dose distributions (29): dose pointkernel convolution, Monte Carlo simulation, and voxel Sfactors. The dose point-kernel is currenfly the most widelyused of these approaches (42,60—63,73,110), primarily because of the demanding computational requirements of

UFem Head OHum Head @L3+L43.0

0'

IC,

0

2

2.5

2.0

1.5

1.0

0.5

1 2 3 4 5PatientNumber

302 THE JOURNALOF Nuci..@ MEDICINE•Vol. 4! •No. 2 •February 2000

111iii: :171 TiIiI6 7 8 9

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A 0.06 B Heterogeneity

005 0.2. 1.E+00

:@â€0̃.04@ C I.E-02

10.03@ 0.02 ‘@1.E-04

0.01 .@11.E-06

0 @B1.E-08

1.E-10

C@ .2E-6 MeanDose (Gy)D 0 20 40 60

1.OE-6 1

@â€8̃.OE-7

@ 6.OE-7 i@ o.i

@ 4.OE-7 I@

2.OE-7-@ 0.01

0.OE+0 Os0 20 40 60 80

Dose (Gy)0.001

0 20 40Dose (Gy)

60 80

FIGURE3. Effectof dosenonuniformityontumorresponse(108).(A) Hypotheticnonuniformdoseto tumorcellpopulationrepresentedby normaldistribution(109) with averageof 40 Gy,SD of 7 Gy,and fractionalSD (FSD)of 7/40 Gy = 0.175. (B)Tumorcell survivalprobabilityfor dose distributionin (A), assumingmonoexponentialtumorcell survivalcurvewith mean lethaldose (D0)of2.85 Gy (i.e., a = 0.35/Gy).Overalltumorcellsurvivalfractionis representedby area undercurve.(C) Overalltumorcellsurvivalfraction as function of dose nonuniformity expressed as FSD of average dose from 0 (i.e., uniform dose) to 0.5 and of average tumordose from 10 Gy (highest curve) to 60 Gy (lowest curve). Tumor cell survival is greater as dose nonuniformity increases. (D)Dose—responsefordosenonuniformity(i.e.,FSD)of0.35, correspondingto pointsintersectingdottedvertical line, is concaveupward.(Adaptedwith permissionof( 108).)

Monte Carlo simulation and the limited availability of voxelS factors. (A dose point-kernel is the radial distancedependent absorbed dose about an isotropic point source inan infinite homogeneous medium [typically a soft tissueequivalent medium such as water].) With the wider availability of high-speed desktop computers and of compatiblesimulation codes, the use of Monte Carlo analysis mayincrease (58,59, 111). Monte Carlo—based dosimetry canmore accurately account for tissue variations in mass densityand atomic number as well as edge effects, which may beimportant at the periphery of the body and at soft tissue—lungand —boneinterfaces (58). For example, if the relevantmicroscopic distribution data were somehow available (e.g.,by autoradiography of biopsy specimens), Monte Carloanalysis might be especially applicable to normal lungdosimetry in radioiodine treatment of metastatic thyroidcancer, particularly in dosimetrically problematic miuiarydisease. This method remains computationally time consum

ing, however (58). Tabulations of voxel S factors, conceptually equivalent to voxel source-kernels (the mean absorbeddose to a target voxel per radioactive decay in a sourcevoxel, both of which are contained in an infinite homogeneous soft-tissue medium) (76, 77), are becoming available(29). In contrast to techniques based on the dose point-kerneland Monte Carlo simulation, the voxel S factor method doesnot require specialized computer facilities and is relativelyfast. Thus, it may emerge as the practical method of choicefor calculation of macroscopic nonuniform dose distributions.

Once a dose distribution has been calculated, a corresponding dose—volumehistogram can be derived. A dose—volumehistogram is a graph of the fraction of the tumor or organvolume receiving a specified dose versus the dose (differential form) or the fraction of the tumor or organ volumereceiving less than a specified dose versus the dose (integralor cumulative form) (Fig. 4). It therefore graphically presents

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0.10

0.08

0.06

the minimum, mean, and maximum doses and the dispersionabout the mean dose. The greater this dispersion, the morenonuniform is the dose distribution.

An important practical component ofmacroscopic nonuniform dosimetry is the ability to fuse, or register, tomographicimages from multiple modalities (67,112—115).Dose distributions, calculated from 3-dimensional activity distributionsmeasured by scintigraphic imaging (i.e., SPECT or PET),may be presented as isodose contours (Fig. 4) or color-codedimages (Fig. 5). By image fusion, such isodose contours orcolor-coded images can be superimposed on or juxtaposedwith the corresponding anatomy to allow correlation ofdoses with tumor and normal organs (as imaged by CT orMRI) (29,60,76,114).

“SENSITIVE―POPULATiONS

The administration of certain radioactive materials, evenin diagnostic amounts, to certain sensitive populations,including pregnant females, nursing mothers, and children,remains a matter of concern in nuclear medicine.

Pregnant FemalesBy modification of the standard anthropomorphic adult

phantom (21,22), increasingly accurate anatomic models ofthe fetus and pregnant female have been developed. Theseinclude models of the pregnant female at the beginning ofpregnancy (representing the embryo as a small unit densitysphere located at the uterus) (116) and at the end of the firstand third trimesters (117). Radiopharmaceutical kinetic datain utero and, therefore, fetal dose estimates are quite limited,however. Published fetal absorbed-dose estimates are generally 0. 1 cGy (0. 1 rad)/37 mBq (1 mCi) administered to themother (116,118-122).

A particularly worrisome issue is radioiodine administration to pregnant females (123,124). The fetal thyroid beginsconcentrating iodine at 12—15wk ofgestation. At 16—24wk,‘31I-iodidedelivers a very large absorbed dose of 1500—6000cGy/37 MBq to the fetal thyroid and an absorbed dose of3—5cGy/37 MBq to the fetal total body, depending on

maternal thyroid uptake (124). For a hyperthyroid therapyadministration of 185 MBq (5 mCi), 7,500—30,000 cGy(rad) would therefore be delivered to the fetal thyroid and

FIGURE4. (A)Dosedistribution,calculatedbyvoxelS factormethodand displayedas color-codedisodosecontourssuperimposedonbremsstrahlungSPECTimageof liver,afterinjectionof32@ chromic phosphate colloid (629 MBq [17 mCi]) into patient

with nonresectable hepatic metastases. Isodose curves areshownfor 10% (yellow),30% (red),50% (blue),70% (orange),and 90% (green)of maximumvoxeldoseof415 Gy (41,500rad).(B)Correspondingdifferentialdose-volumehistogram.(C)Corresponding integral dose-volume histogram. Abscissa axes ofhistogramswere truncatedat 200 Gy (20,000rad) becausesuchsmall fraction of liver receiveddoses in excess of this dose. Asshownby dotted lines, “ideal―differentialand integraldosevolume histogramwould be vertical line and rectangle, respectively, indicating that entire tumor or tissue received uniformsingledose. (Adaptedwith permissionof (29).)

15—25rad to the fetal total body. Not surprisingly, withradiogenic destruction of the fetal thyroid and thyroidhormone deficiency in utero, fetal hypothyroidism andcongenital cretinism have been shown to result after radio

B 0.14

@ 0.12

I

1:::AbsorbedDoee(Gy)

/

j4 —Idsaldiftsrentialdos.@volum.histogram

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0.00

C

I75 100 125

AbsorbedDoee(Gy)

304 THE Joui@L OF NUCLEARMEDICINE •Vol. 41 •No. 2 •February 2000

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C

IS

FIGURE5. (A) Seriesof transverseCTimagesthroughliver(blueregionof interest[AOl])of patientwithcolorectalcarcinomaand largehepaticmetastasis(greenAOl).(B) Correspondingseries of transverseSPECTimagesafteradministrationof 1311..CC49anti-TAG-72murinemonoclonalantibody ( 132)show liver activitydelineatedbyblue AOl and tumoractivitydelineatedbygreen AOl. (C) Dose distributionIn hepaticmetastasis,calculatedbyconvolutionofphotonpoint-kernelwith3-dimensionalactivity distribution and by assuming completeintravoxel@3-rayabsorption.Imagesaredisplayedas “thermal―colorcoded,from blackrepresenting0 dose to white representingmaximumdoseof0.10Gy—37MBq(10rad/mCi). (D) Integral dose—volumehistogram.(Adaptedwithpermissionof (114).)

D100

80

E

>20

00.02 0.04 0.06 0.08 0.1

Absorbed Dose (GyImCi)

iodine therapy of hyperthyroidism or thyroid cancer inpregnant females. It is therefore critical to avoid radioiodineadministration to the pregnant patient, even in diagnosticamounts.

NursingMothersDiagnostic radiopharmaceuticals administered to lactat

ing women can achieve high concentrations in breast milkand deliver potentially significant radiation doses to nursinginfants (125—128).For example, the cumulative breast milkactivity ranged from 0.03% to 27% ‘@‘Iadministered to 6women for thyroid uptake studies (129). Using a variety ofdosimethc criteria (e.g., an effective dose equivalent to thenursing infant of 0.1 cSv [10.1 rem]), several authors have

recommended different interruption periods before resumingbreast-feeding after administration of radiopharmaceuticals.Although there is no absolute consensus, the following arerepresentative of the published recommendations: 24 h afterany administration of @‘Tc,2—4wk after administration of67Ga-citrate, and permanently for the current nursing infantafter any administration of ‘@‘I(125—128).

ChildrenWith the publication of the week by Christy and Ecker

man (21), anthropomorphic models are now available fornewborns and 1-, 5-, 10-, and 15-y-old children. Using theMIRDOSE 3.1 computer program and available kinetic datain conjunction with these models, Stabin and Gelfand (130)

RADIATION Dosm@iE@ri@Y•Zanzonico 305

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@:@

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