Radiobiology and Radiation Dosimetry in Nuclear Medicine Massimo Salvatori, Marta Cremonesi, Luca Indovina, Marco Chianelli, Massimiliano Pacilio, Carlo Chiesa, and Pat Zanzonico Contents Radiobiology ......................................... 4 Conventional Radiobiological Models ............... 4 Cell Death Mechanisms ............................... 5 Possible Contributing Mechanisms to RNT Tumor Responses ......................................... 6 Low-Dose/Dose-Rate Apoptosis ...................... 6 Low-Dose Hyper-radiosensitivity–Increased Radioresistance .................................... 6 G2 Synchronization, Bystander, and Cross-Fire Effects ............................................. 7 Adaptive Responses ................................... 7 Fractionated RNT and Hypoxia ....................... 8 Future Directions ...................................... 8 Dosimetry: Overview on Methods .................... 8 Clinical Experience ................................... 10 131 I-Iodide Therapy of Differentiated Thyroid Carcinoma ......................................... 11 Peptide Receptor Radionuclide Therapy ............. 14 Radioimmunotherapy of Lymphoma ................. 18 Radioembolization of Liver Tumors ............... 20 Therapy of Neuroendocrine Malignancy ............. 23 Treatment of Metastatic Bone Pain ................... 26 Biological Dosimetry ................................. 27 Assays in Biological Dosimetry ...................... 28 Chromosome Painting ................................ 29 Comet Assay .......................................... 29 γ-H2AX ............................................... 30 Conclusions ........................................... 30 Diagnosis .............................................. 30 Medical Radiation Exposures: Societal Concerns .... 31 Radiation Doses in Diagnostic Nuclear Medicine .... 31 Multimodality Studies: PET/CT and SPECT/CT ..... 33 Dose–Response Relationships in Radiation Carcinogenesis .................................... 34 Risk–Benefit Considerations .......................... 35 Considerations for Sensitive Populations: Prospective Parents, Pregnant Women, and Nursing Mothers .............................. 36 Nursing Mothers ...................................... 37 References ............................................ 38 M. Salvatori (*) Nuclear Medicine Institute, Catholic University of the Sacred Heart – Policlinico A. Gemelli, Rome, Italy e-mail: [email protected]; [email protected]M. Cremonesi Department of Medical Physics, European Institute of Oncology, Milan, Italy e-mail: [email protected]L. Indovina Department of Medical Physics - Policlinico Universitario A. Gemelli, Rome, Italy e-mail: [email protected]M. Chianelli Department of Endocrinology, Ospedale Regina Apostolorum, Albano, Rome, Italy e-mail: [email protected]M. Pacilio Department of Medical Physics, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy e-mail: [email protected]C. Chiesa Nuclear Medicine Department, National Cancer Institute, Milan, Italy e-mail: [email protected]P. Zanzonico Memorial Hospital Research Laboratories, Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA e-mail: [email protected]# Springer International Publishing Switzerland 2016 H.W. Strauss et al. (eds.), Nuclear Oncology , DOI 10.1007/978-3-319-26067-9_6-1 1
Transcript
Radiobiology and RadiationDosimetry in Nuclear Medicine
Massimo Salvatori, Marta Cremonesi, Luca Indovina,Marco Chianelli, Massimiliano Pacilio, Carlo Chiesa, andPat Zanzonico
M. Salvatori (*)Nuclear Medicine Institute, Catholic University of theSacred Heart – Policlinico A. Gemelli, Rome, Italye-mail: [email protected];[email protected]
M. CremonesiDepartment of Medical Physics, European Institute ofOncology, Milan, Italye-mail: [email protected]
L. IndovinaDepartment of Medical Physics - Policlinico UniversitarioA. Gemelli, Rome, Italye-mail: [email protected]
M. ChianelliDepartment of Endocrinology, Ospedale ReginaApostolorum, Albano, Rome, Italye-mail: [email protected]
M. PacilioDepartment of Medical Physics, Azienda Ospedaliera SanCamillo Forlanini, Rome, Italye-mail: [email protected]
C. ChiesaNuclear Medicine Department, National Cancer Institute,Milan, Italye-mail: [email protected]
P. ZanzonicoMemorial Hospital Research Laboratories, Department ofMedical Physics, Memorial Sloan-Kettering CancerCenter, New York, NY, USAe-mail: [email protected]
# Springer International Publishing Switzerland 2016H.W. Strauss et al. (eds.), Nuclear Oncology,DOI 10.1007/978-3-319-26067-9_6-1
AbstractRadionuclide therapy (RNT) uses systemi-cally administered radiopharmaceuticalsdirected to a specific cancer-associated targetto provide low-dose-rate (LDR) treatment.The radiation dose is delivered to the tumorcells by continuous, but declining, exposurethat is a function of the initial uptake and thevariable half-life. The average dose rate forRNT is typically of the order of 2–8 Gy/day,and the maximum absorbed dose may be up to50 Gy delivered over a period of many days.This is in marked contrast to the situation withexternal beam radiotherapy (EBRT), wherethe dose is delivered at a high-dose rate(HDR), typically 1–5 Gy/min, and also incontradistinction to the dose rate at whichbrachytherapy is delivered, typically 1–5 Gy/h. The mechanisms by which cells respond toLDR exposures are fundamentally differentfrom those occurring at HDR. LDR exposurestend to promote loss of clonogenic potential insome cell types (e.g., lymphomas) by activat-ing apoptotic responses, whereas high dosestend to cause necrosis as their primary mech-anism of cytotoxicity. The ability to induceapoptosis varies inversely with dose rate.Many cell types exhibit an initial hypersensi-tive response at doses below �25 cGyfollowed by a region of increasing radio-resistance up to �50 cGy. This phenomenonprobably involves an alteration in the cellularprocessing of DNA damage as a function ofdose. Radiation damage to cells is due primar-ily to indirect effects such as formation of freeradicals in water (with their diffusion andsubsequent interaction with cellular compo-nents, mostly DNA) and to some degree directdamage to DNA. Different tissues and differ-ent individuals have different abilities torespond to and repair this damage. The valueof LDR therapy with radionuclides in patientswith differentiated thyroid carcinoma,somatostatin receptor-expressing tumors,neuroendocrine tumors, lymphoma, livertumors, and treatment of metastatic bonepain is discussed.
KeywordsRadionuclide therapy • Radiobiology • Radia-tion dosimetry • Therapeutic radiopharmaceu-ticals • DNA damage and radiation dose
Magnetic resonance imagingPRRT Peptide receptor radionuclide
therapyRBE Relative biological
effectivenessRE Relative effectiveness per unit
doseRILD Radio induced liver diseaseRIT RadioimmunotherapyROI Region of interestROS Reactive oxygen speciesSF Surviving fractionSNM Society of Nuclear Medicine
ligandVOI Volume of interestWBD Whole-body radiation doseWBS Whole-body scanγ-H2AX Phosphorylated member X of
the H2A histone family
New radiopharmaceuticals have led to increasingsuccess of radionuclide therapy (RNT) [1, 2]. Toplan treatment with RNT requires understandingdosimetry to both the target organ and other sites oftracer localization [3, 4]. However, despite the factthat maximizing radiation-absorbed dose to tumorwhile minimizing damage to normal tissues is thecentral objective of RNT, up till now RNT dosim-etry has not gained wide acceptance as a necessaryclinical tool. The need for dosimetry to individuallyoptimize the therapeutic activity to be administeredhas been far from self-evident, and efforts in thisdirection are in an infancy stage [4].
This chapter describes the progress that hasbeen achieved in the fields of dosimetry andradiobiology, including a brief overview of thetechniques used in biological dosimetry.
Radiobiology and Radiation Dosimetry in Nuclear Medicine 3
Radiobiology
There are three major approaches to the deliveryof radiation therapy to treat patients with cancer:(1) locoregional delivery, such as in external beamradiotherapy (EBRT), (2) sealed-source intersti-tial/intracavitary radiotherapy (brachytherapy),and (3) RNT which include the use of receptor-directed ligands, metabolic precursors, or mono-clonal antibodies (i.e., radioimmunotherapy) [5].
The key clinical and basic characteristics ofRNT are the systemic administration of a radio-pharmaceutical directed to a specific cancer-associated target and the rate at which the radia-tion dose is delivered to that target [5].
According to the principle of very low-doserate (LDR), in RNT the radiation dose is deliveredto the tumor cells by continuous, but declining,exposure that is a function of the initial uptake andthe variable half-life. The average dose rate forRNT is typically of the order of 2–8 Gy/day, andthe maximum absorbed dose may be up to 50 Gydelivered over a period of many days. This is inmarked contrast to the situation with EBRT, wherethe dose is delivered at a constant high dose rate(HDR), typically 1–5 Gy/min, and also at variancewith the dose rate brachytherapy is delivered,1–5 Gy/h [5].
To date, most radiobiological models of RNThave been based on the extrapolation of data ob-tained following homogeneous exposures to acutesingle or fractionated doses of EBRT and haveassumed that EBRT and RNT administered aresubstantially equivalent from the biological pointof view. However, emerging evidence suggeststhat the mechanisms of cellular response to LDRexposures are fundamentally different from thoseoccurring at HDR with either EBRT or brachy-therapy [3, 6].
The combination of prolonged response, lim-ited toxicity, and the ability to treat on multipleoccasions suggests that the mechanism of actionof LDR therapies is different from that seen withHDR exposures. Accordingly, treatment plans, clin-ical trials, and outcome assessment should bedesigned to consider this difference. Current radio-biological research points to a way in which RNTcan be more effectively administered to patients by
taking into account the biology of themechanism ofaction of therapy as well as the physical character-istics of the radionuclide [5].
Conventional Radiobiological Models
A number of basic principles, emerged from earlystudies describing the effects of acute single orfractionated doses of EBRT on the clonogenic sur-vival of cells, generally held that a cell must be“hit” by a radiation track in order to be killed, thatgenomic DNA was the principal “target” for kill-ing, and that double-strand breaks (DSBs)/clus-tered lesions/multiply damaged sites were theprincipal DNA lesions leading to cell death [3].
Early models focused largely on the mechani-cal or metabolic challenges that DSBs might poseto a cell when it attempts to replicate its DNA(in S-phase) or divide (inmitosis). The linear-quad-ratic (LQ) model of fitting and interpreting clono-genic cell survival curves became a cornerstone ofexperimental radiation oncology and indeed is stillwidely used for predicting the clinical impact ofchanges in dose fractionation or dose rate on bio-logical effect [5].
This model assumes two components of cellkilling, one proportional to the dose D (αD) andthe other is a quadratic term (βD2) in which twosublesions are presumed to interact to produce alethal event. The relationship between cell survival(surviving fraction, SF) and dose is then described
by: �ln SF½ � ¼ αDþ βD2 . The two-hit/quadratic(β) term represents the fraction of cell killing causedby damage that can be spared either by dose frac-tionation or by decreasing the dose rate. In contrast,the one-hit/linear α-type lethal events are indepen-dent of time and thus of fractionation or dose rate[3, 5].
Application of the LQ model to HDR expo-sures indicates that cell killing generally decreasesas the dose is fractionated, and this sparing wouldreflect the repair that takes place between fractionsof the individual “sublethal” lesions that, in com-bination, would otherwise have contributed to β-type cell killing. Survival curves for large numbersof small fractions ultimately approximate the initialslope (α) of the HDR curve.
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The typical dose rates used for both clinicalEBRTand radiobiological studies are of the order ofminutes (�1–5 Gy/min), exposure times not longenough for DNA repair to occur during the irradia-tion process. As the dose rate is lowered, the timetaken to deliver a given dose increases, and it isthen possible for DNA repair to take place duringirradiation and for radiosensitivity to graduallydecline [3, 5].
Survival curves at decreasing LDR becomestraighter and ultimately extrapolate the initialslope (α) of the HDR curve, with a sparing effectthat would be attributed to the repair of sublethallesions occurring during the protracted exposure(Fig. 1).
At very LDRs (�2 cGy/min), cell proliferationcan occur during the irradiation, thus leading torepopulation of the pool of clonogenic cells. Clear-ly, based on this assumption, RNT should be inef-fective, although this expectation is not consistentwith many clinical observations. Such phenome-non, in which decreasing the dose rate results inincreased cell killing, has been defined “inverse
dose-rate effect.” The effect has been attributedboth to the lower-dose rate (permitting the cells toprogress through the cell cycle into more radiosen-sitive phases) and to some hypersensitivity of cellsto low-dose/LDR exposures, as will be discussedbelow [3, 5].
Cell Death Mechanisms
Most cellular responses to ionizing radiation-induced DNA damage are genetically regulatedand involve specialized DNA damage-recognitionfactors that trigger a cascade of signaling eventsthat alter the expression and/or activity of specificgenes/proteins involved in cell cycle arrest, DNArepair, accelerated senescence, and apoptosis atthe cellular level and in tissue repair at the tissuelevel [5].
Necrosis, a form of cell death that has beenvariously described as generalized, nonspecific,accidental, or passive (i.e., it is not a geneticallyregulated process), generally occurs after high doses
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Fig. 1 Conventional dose-rate effect for cell killing asthe dose rate is loweredfrom 150 to 1.6 cGy/min.The dashed curvesrepresent the best fit to thedata set obtained using thelethal–potentially lethal(LPL) model assumingeither full repair (a) or norepair (b), respectively
Radiobiology and Radiation Dosimetry in Nuclear Medicine 5
in cells that enter mitosis carrying high levels ofunrepaired DNA damage [5].
In contrast, apoptosis is an energy-dependent,genetically controlled “suicide” process that in-volves the activation of degradative proteolyticenzymes called caspases and tends to occur atlow doses of radiation. Apoptotic postirradiationcell death is mediated by two pathways, both re-sulting in activation of the cascade of caspases thatfunction as cell executioners. Firstly, signals fromthe nucleus or cell membrane can activate the“intrinsic” pathway of apoptosis with a series ofsequential events that cause final activation ofcaspases 3,6,7, and 8. Secondly, the “extrinsic”pathway of apoptosis ismediated by death receptorsthat are activated by ligands, such as the Fas ligand,tumor necrosis factor-α (TNF-α), and TNF-relatedapoptosis-inducing ligand (TRAIL). TRAIL inducesapoptosis in response to ionizing radiation throughthe clustering of DR4 and DR5 receptors in the cellmembrane [7].
Other modes of cell death are the “accelerated”or “premature” senescence or “STASIS” (stress oraberrant signaling-induced senescence), a geneti-cally programmed response to DNA damage [8],and the mitotic catastrophe, generally defined asthe failure of a cell to properly undergo mitosisafter DNA damage. It has recently been recog-nized that mitotic catastrophe is not a mode of celldeath per se, but a death that generally occurssecondarily to mitotic catastrophe, apoptosis, oraccelerated senescence [9]. Death secondary tomitotic catastrophe has been suggested to accountfor a significant proportion of the cytotoxicityobserved after radiation exposure.
Possible Contributing Mechanismsto RNT Tumor Responses
Low-Dose/Dose-Rate Apoptosis
Different mechanisms of cytotoxicity appear tooperate in different dose and dose-rate ranges fora given cell type. Indeed, several experimentalstudies support the tenet that LDR exposures tendto promote loss of clonogenic potential in some celltypes (e.g., lymphomas) by activating apoptotic
responses, whereas high doses tend to cause necro-sis as their primarymechanism of cytotoxicity [10].For example, low doses of EBRT induce substan-tial apoptosis in tumor cells and that thedose–response curve for apoptosis plateaus above�7.5 Gy [11]. Furthermore, multiple small frac-tions of EBRTwere found to produce a higher levelof apoptosis than a large single dose. Clinical effec-tiveness of lower doses of RNT and other LDRtherapies could be related to their ability to opti-mize such effects, such as apoptosis exhibiting aninverse dose-rate effect [5].
Many cell types exhibit an initial hypersensitiveresponse at doses below �25 cGy, followed by aregion of increasing radioresistance up to�50 cGy,the survival curve above 1Gy closely following theexpected LQ response [12]. This phenomenon,illustrated in Fig. 2, has become known as the“low-dose hyper-radiosensitivity–increased radio-resistance” (LDH–IRR) response. The mechanism
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Fig. 2 Cellular survival responses of two normal humanfibroblast strains, GM38 and GM10, following exposure to60Co γ-radiation
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of LDH–IRR probably involves an alteration in thecellular processing of DNA damage as a functionof dose. One possibility is that the transition fromLDH to IRR may involve the activation of radio-protective DNA-repair pathways that are triggeredby a certain threshold level of DNA damage. Cellswould then be hypersensitive to low doses of radi-ation that produce insufficient DNA damage totrigger this protective process.
LDH–IRR seems to be preferential and possi-bly limited to a fraction of cells in the G2 phase ofthe cell cycle, and an important consequence ofthe LDH–IRR response is that the conventionalLQ model greatly underestimates cellular radio-sensitivity after acute low doses. This limitationwas addressed by Joiner et al. [12] in a modifiedLQ model that incorporates the impact of aninduced repair threshold.
If the LDH–IRR response occurs also duringLDR therapies, the latter could exert much greatercytotoxicity per unit of absorbed dose than wouldbe predicted by the conventional LQ model. TheLDH–IRR model leads to the prediction thatDNA-repair processes should be less efficientafter doses below the IRR threshold (i.e., typically�40 cGy) if this response is related to inducedDNA repair.
In some tumor cell lines, LDR exposures in therange of 10–300 cGy/h have been shown to causethe partial synchronization of cells in the G2/Mphase as a result of the prolonged activation of theG2 checkpoint [13]. This effect could have twoconsequences for LDR therapies. Firstly, it mightabrogate the competitive effects of proliferationon the elimination of clonogenic tumor cells. Sec-ondly, it might enhance the relative effectivenessof LDR radiation by holding the cells in G2,which is a relatively radiosensitive phase of thecell cycle, a mechanism that was invoked toexplain the inverse dose-rate effect seen in somecell lines at LDR.
The “bystander” effect refers to the phenome-non whereby manifestations of damage (such as
cell death) are observed in cells adjacent to thosethat are traversed by an ionizing particle but thatare not themselves “hit” [5]. This means that acytotoxic response in the presence of the by-stander effect will be greater than that predictedon the basis of classical dosimetric estimates. Thebiological bystander effect appears to reflect thegeneration of a “damage signal” emanating fromirradiated cells that is communicated to the non-irradiated adjacent cells through a variety of sig-naling mechanisms. These include intercellularcross talk, the release of reactive oxygen species(ROS) or of clastogenic factors, and intracellularsignal transduction pathways. The contributionfrom these mechanisms probably varies amongdifferent model systems, leading to some contro-versy as to their relative importance.
The bystander effect is quite distinct from thecross-fire effect, another mechanism of RNT, inwhich an ionizing particle emanating from a sourceradionuclide in one cell deposits its energy in adistant target volume represented by a neighboringor distant cell [13]. Cross-fire effects depend pre-dictably on the particle range and play a major rolein the effectiveness of RNT using β-emitting iso-topes such as those generated by 131I that have arange of millimeters in tissue. Such cross-fireeffects with β-emitters are also important for ther-apeutic responses, because they should help toovercome the limitations imposed on RNT by het-erogeneity in the distribution of the radiopharma-ceutical within the tumor mass, which is especiallyimportant in solid tumor.
Adaptive Responses
The in vitro adaptive response is the phenomenonwhereby exposure of cells to a low “priming” doseof radiation induces resistance to a subsequenthigher-dose exposure [14]. Like LDH–IRR, theadaptive response has been suggested to involveinducible radioprotective mechanisms, such asDNA-repair pathways, although not all studiesare consistent with such a mechanism. A possibleexplanation for these diverse findings is the broadrange of cell types, assays, priming treatments,and times of observation employed in different
Radiobiology and Radiation Dosimetry in Nuclear Medicine 7
studies; furthermore, adaptive responses typicallyoccur only within a narrow dose range of�0.5–20 cGy. With respect to the potential roleof adaptive responses in RNT, it has been notedthat LDR irradiation can be regarded as a series ofpriming doses briefly separated in time; the adap-tive response could, therefore, have a negativeinfluence on the efficacy of LDR therapies, unless,of course, it is not activated under these conditions.
Fractionated RNT and Hypoxia
Fractionated delivery of RNT is designed mostly tocompensate for the anticipated heterogeneity ofRNT dose distribution, which determines absentor suboptimal intratumoral radionuclide deposition,an event that is especially important in large, poorlyvascularized tumors that contain regions of hypoxia[10]. The development of hypoxia in tumors isbelieved to represent a major barrier to successfulEBRT, in part because hypoxic cells are�threefoldresistant to acute exposures to ionizing radiationwith respect to normoxygenated cells [15]. Conven-tional dose fractionation partially overcomes thenegative effect of hypoxia, by allowing for thereoxygenation of hypoxic cells between fractions,and it is reasonable to assume that the same wouldbe true for protracted LDR therapies. Under someconditions, fractionated delivery of radiolabeledantibodies and peptides has shown efficacy, withfractionated delivery causing less toxicity than asingle administration. In general, both preclinicalmodels and clinical radioimmunotherapy (RIT)evidence suggest that RNT fractionation results ina beneficial effect and in a more uniformradiation dose distribution. This has certainly pro-ved to be an effective strategy with 131I-meta-iodobenzylguanidine (131I-MIBG), with obviousincreases in clinical effectiveness, and there arenow data to support the use of fractionated treatmentwith radiopeptides as a way of reducing toxicity.
Future Directions
There is no doubt that a better understanding ofthe radiobiology andmechanisms of action of RNT
will facilitate the development of newer radio-pharmaceuticals and the design of prospectivephase III and IV clinical trials [5]. Although ourunderstanding of the low-dose-related phenomenahas increased dramatically in the last few years, it isimportant to validate these effects in the clinicalsetting. In particular, validation of a role for thebystander effect in RNT in vivo will impact theassessment of therapeutic response to RNT, as wellas risk estimates for therapeutic and diagnosticradiopharmaceuticals. In addition, application ofhigh-throughput genomic/proteomic screeningme-thods (DNA arrays, single nucleotide polymor-phism analysis, and protein arrays) will allow arapid and accurate prediction of patient response,both in the tumor and in normal tissues [5]. Otherissues, such as the role of metabolic markers inselecting therapies and dosage schedules, and thepotential interactions between low-dose chemo-therapy and RNT, constitute additional importantareas for clinical development.
Dosimetry: Overview on Methods
The basic goal of RNT is to deliver enoughradiation-absorbed dose to the tumor while mini-mizing the risk of toxicity to the bone marrow andto other normal tissues. For RNT, many physiciansadminister approximately the same activity to allpatients, while ideally administered activity shouldbe adjusted using a patient-specific treatment plan-ning strategy based on radiation-absorbed dose.With a patient-specific approach, activity adminis-tration is optimized to maximize treatment efficacywhile minimizing deleterious side effects to normalorgans.
In RNT the absorbed dose is the energy depos-ited (E) per unit mass of matter (m) (with units ofJ/kg, 1 J/kg = 1 Gy). In RNT, E is the number ofradionuclide disintegrations in a particular vol-ume multiplied by the energy emitted per disinte-gration of the radionuclide and the fraction ofemitted energy that is absorbed by a particularmass (m).
To improve the correlation between dose and theexposure effect, other quantities must be defined,such as relative biological effectiveness (RBE),
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radiation weighting factors, and tissue weightingfactors. This suggests that energy absorbed perunit mass does not predict response at all levels,and some other factors must be considered.
Damage to cells is due primarily to indirecteffects of radiation (formation of free radicals inwater that diffuse and subsequently interact withcellular components, mostly DNA) and to somedegree to direct effects (direct damage to DNAfrom radiation interaction). Also, different tissuesand different individuals have different abilities torespond to and repair this damage. Thus, physicalquantities such as the absorbed dosemust be linkedto radiobiological quantities to completely under-stand and be able to predict effects in a system.
Internal dose can be calculated by the follow-ing simple equation from the medical internalradiation dose (MIRD) Committee of the Societyof Nuclear Medicine (SNM) [16, 17]:
DT�S ¼ A! � Δ� ϕT�S
MT
¼A! � S ¼ A0 � τ � S
(1)
where D is the absorbed dose in a target organ(Gy), à is the cumulated activity in source regionS, Δ is the energy emitted by the radionuclide perdisintegration, ϕT!S is the fraction of energyemitted by the radionuclide in source regionS that is absorbed in the target region, and MT isthe mass of region T. Furthermore, τ is the resi-dence time, which is simply equal to à /A0, thecumulated activity divided by the patient’s admin-istered activity (A0). S is the absorbed dose perunit cumulated activity and it is given by
S ¼ Δ� ϕT�SMT
(2)
Equation 1 means that the absorbed dose dependson the half-life of the radionuclide and its spatialand temporal distribution in the target. The latterare typically obtained by images collected atdifferent times after administration of the radio-pharmaceutical and used to estimate the amountor concentration of radioactivity in a specificregion. The level of activity obtained at differenttimes after injection, plotted against time, gives a
time–activity curve for a particular target, such asan organ or tissue. The integral of this curve givesthe total number of disintegrations or the cumu-lated activity (Ã) for the region. Therefore, themain input data needed for evaluation of radiationdose are the biokinetic data that characterize thedistribution and retention of the radiopharmaceu-tical throughout the biological system.
This absorbed dose could be used to estimatethe biologic effective dose (BED) [18]:
BED ¼ D� REwhereRE ¼ 1þ Dλ
α=βð Þ μþ λð Þ� �
(3)
where D is the absorbed dose, μ is the exponentialrepair rate constant that quantifies the rate of sub-lethal damage repair, and λ is the effective clear-ance rate constant (given by the sum of thephysical decay and the biological clearance rateconstants). It means that the BED may be definedas the product of the total physical dose D and amodifying factor named the relative effectivenessper unit dose, RE, that quantifies dose-rate effectswith respect to radiosensitivity and repair of radi-ation damage.
The BED equation is derived from the linear-quadratic (LQ) model that describes the survivingfraction (Sf) of target cells after a radiation dose(D):
Sf ¼ exp �αD� βD2� �
where the linear component αD describes theDSBs induced by a single ionizing event, andthe quadratic component βD2 describes thesame effect induced by two separate ionizingevents; α and β are the tissue-specific coefficientsfor radiation damage, α being proportional todose (one single event is lethal) and β beingproportional to squared dose (two sublethalevents required for lethal damage). The α/βratio is also named “repair capacity” and quan-tifies the sensitivity of a given tissue to changesin fractionation. Typical values for the α/β ratioare about 5–25 Gy for early-reacting normal tis-sues and tumors and about 2–5 Gy for late-responding normal tissues.
Radiobiology and Radiation Dosimetry in Nuclear Medicine 9
Also with the biological effective dose, thefocus in radionuclide dosimetry study is to calcu-late the absolute amount of energy delivered permass unit of tissue, i.e., the absorbed dose D.
In order to plan and design an appropriatedosimetric study, it is necessary to know approx-imately how the compound will be taken up andcleared from various organs and the whole body,by collecting multiple samples. Most therapeuticagents have a relatively fast phase of organ uptakeand initial clearance, followed by more generalsystemic removal that lasts for many days. There-fore, a typical sampling scheme is to collect sev-eral samples in the first hours after administrationand then about once or twice a day for a few daysto several weeks.
To calculate the cumulated activity, the integralof the time–activity curve for each source organmay be obtained by (1) direct integration of data,for example, with the trapezoidal method, (2) a fitof the data to yield a mathematical expression ofthe uptake and retention in the target organ, and(3) using compartmental models, if the pharma-cokinetics inside the target tissue is available.
Specific quantification techniques have beensummarized for 2D and 3D imaging in theMIRD16 and MIRD 17 [19, 20]. Using planardata (2D imaging), the most accepted technique isto obtain images from the posterior and anteriorprojections and then correct the projected data ineach region of interest (ROI) for attenuation andscatter. The most popular technique for attenuationcorrection involves the use of a Cobalt-57 (or otherappropriate radionuclide) projection source imagedwith and without the patient in the view, the atten-uation coefficient for the system having been char-acterized in advance. For scatter correction, thetwo- or three-energy window method is widelyaccepted and applied when gamma camera soft-ware permits simultaneous acquisition in multipleenergy windows. One of the best known packagesable to offer mean absorbed doses in the organs,based on uniform activity distribution in organs/tissues, was the MIRDOSE3.1 package that imple-mented the use of whole-body MIRD-stylizedmathematical phantoms representing adult malesand females, children, and pregnant women [21].The MIRDOSE3.1 software could be used for
calculating internal dose for a large number ofradiopharmaceuticals, the rapid comparison of cal-culations for different cases, examination of dosecontributions to different organs, and regional mar-row dose calculations.
MIRDOSE3.1 has been updated to a new gener-ation code, Organ Level Internal Dose Assessment(OLINDA), employing the Java programming lan-guage and the Java Development Kit environment[22]. The entire code was rewritten, but all of thebasic functions of the MIRDOSE code wereretained, while others were extended. More individ-ual organ phantoms were included, the number ofradionuclides was significantly increased (includingalpha emitters), and the ability to perform minorpatient-specific adjustments to doses reported forthe standard phantoms was made possible.
Quantitative 3D imaging using single-photonemission computed tomography (SPECT)methodsis considerably more complex. The essential re-quirements for 3D imaging-based dosimetry arethe availability of 3D anatomic imaging studies,such as CT or MRI, at least one 3D imaging studyof the radioactivity distribution (e.g., PET orSPECT), and software that implements a point-kernel or Monte Carlo calculation methodology toestimate the spatial distribution of absorbed dose.Two fully developed packages are 3D-InternalDosimetry (3D-ID) and DOSIMG [23, 24].
Clinical Experience
Clinical applications of dosimetry are not widelyadopted in RNT, mainly because data from pro-spective randomized clinical trials that may provethe effectiveness of dosimetry in predicting clini-cal outcome after treatment are lacking. In order toprove that dosimetry-based RNT is of additionalbenefit over administration of fixed empirical activ-ities or activities per body weight, prospective ran-domized phase III trials with appropriate endpointsshould be undertaken [25]. So far, the lack of stan-dardized methodology for calculating the absorbeddoses and the continued use of approaches based onadministrations of fixed empirical activities irres-pective of personalized radiation dose estimates hashampered efforts to compare clinical outcomes in
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different patient populations and has led to signifi-cant difficulty in comparing results among differenttrials [4].
131I-Iodide Therapy of DifferentiatedThyroid Carcinoma
Radioiodide therapy has largely been proven to bea safe and effective method in the treatment ofpatients with DTC after total or near-total thyroid-ectomy [26]. Nevertheless, although it has beenshown to be useful for ablation of thyroid rem-nants and for treatment of locoregional or distantmetastases, at present there is no consensus on theactivity of 131I-iodide to administer, because ofthe lack of prospective, randomized data [27].Many excellent reviews of empiric fixed pre-scribed activity have been previously published,and the most frequently used sets of empiric fixedprescribed activities range from 1.1 to 5.5 GBq forablation to 5.5–11.0 GBq for treatment of metas-tases [28].
The advantages of using the empiric fixed pre-scribed activity are convenience, a long history ofuse, an acceptable rate and severity of complica-tions, and the possibility to avoid the “stunning”phenomenon due to the diagnostic 131I-iodideactivity [27].
However, the persistence of disease in a signif-icant proportion of patients and the possibility formultiple small empiric activities to have less ther-apeutic benefit than the same total activity given atone time have led to attempts to improve suchempiric approach to therapy [28].
Efforts to meet this goal have led to two basicdosimetrically determined prescribed activity ap-proaches, each one addressing a different aspect ofthis problem. Benua et al. developed an approachto define the maximum activity of radioiodide thatcan be administered without significant bone mar-row suppression [29]. Maxon developed a methodto evaluate the activity of radioiodide needed toadequately treat metastatic lymph nodes [30].
The limited bone marrow toxicity method(Benua approach) was developed at the MemorialSloan Kettering Cancer Center, by setting an upperlimit for the radiation dose to the patient’s blood,
which is considered as a surrogate for the criticalorgan, i.e., the red bone marrow [29].
Since radioiodide concentration is almost iden-tical in blood as in inner organs including the redbone marrow, assessing the blood absorbed doseallows to estimate the radiation-absorbed dosethat will be delivered to the hematopoietic systemof the individual patient during therapy [30]. Asummary of the methodologies used can be foundin the review article by van Nostrand [28] andin the guidelines of the Dosimetry Committee ofthe European Association of Nuclear Medicine(EANM) for pre-therapeutic dosimetry [31].
The method allows estimation of the radiationdose that will be delivered to the hematopoieticsystem per unit activity administered to a givenpatient and restricts such dose to no more than2 Gy to the blood [29, 31]. Therefore, the maximumactivity for treatment is calculated as the amount of131I-iodide that would deliver an absorbed dose of2 Gy to the blood compartment [32].
This method requires evaluation of the kineticsof activity in the blood and in the whole body,obtained by conjugate views of a whole-bodyscan (WBS) acquired with a dual-head gammacamera equipped with high-energy collimators[28].
To evaluate the blood kinetics, five bloodsamples should be obtained over 1 week (e.g., at2, 6, 24, 96, and 144 h) after administration of131I-iodide, and the blood activity should be mea-sured in a calibrated well counter from aliquots ofblood samples [28].
The first WBSmeasurement obtained 2 h aftertracer administration represents 100% of admin-istered activity, while measurements are repeatedat 24, 48, 72, and 96 h (or later if uptake and/orrenal clearance is delayed). As an alternative toWBS conjugate-view imaging obtained with agamma camera, measurements with an externalprobe can be used [28].
To calculate the whole-body activity as afunction of time and circulating activity per mLof blood, the geometric mean of correspondingnet counts obtained by conjugate views and allblood activities are normalized to the first datapoint and to the administered activity, respec-tively [28, 31].
Radiobiology and Radiation Dosimetry in Nuclear Medicine 11
The curves, A(t), describing the activity in theblood and in the total body as a function of timeafter the administration are usually multi-expo-nential, and bi-exponential fitting is usually ap-propriate to determine the function describingtime–activity curves in the blood and in the totalbody, respectively.
The residence times in the whole body andactivity concentration in blood, τTotalBody[h] andτBlood[h], are calculated by integrating the cor-responding retention function R(t) = A(t)/A0.
According to the generally accepted MIRDformalism, the mean absorbed dose to the bloodper unit administered activity is determined by thesum of contributions of blood self-irradiation andof penetrating radiation from the whole body.
The mean blood absorbed dose per unit admin-istered tracer activity can therefore be calculated as
�DBlood
A0
Gy
GBq
� �¼ 108� τBlood h½ � þ 0:0188
wt kg½ �� τTotalBody h½ �
The activity to be administered for a bloodabsorbed dose of 2 Gy is
AAdm GBq
� � ¼ 2� A0 Gy=GBq½ �DBlood
Under the conservative assumption that the activ-ity concentrations within the hematopoietic tissueand the blood are identical [33], a red marrow-based approach for the determination of the max-imum activity to be administered has been pro-posed [33]. Although this method seems to beaccurate, no systematic clinical validation of thered marrow absorbed dose versus toxic effect hasyet been undertaken.
The limited bone marrow dosimetry is easy toperform both pre-therapeutically and peri-thera-peutically, thus allowing administration of addi-tional activity for selected patients without risk ofsevere side effects. However, the original methodmight not to be applied in the presence of extendedmetastatic bone involvement, as the blood-basedabsorbed dose calculation could underestimate theabsorbed dose to the red marrow. Similarly, it
should be carefully applied also in the case ofpatients with diffuse lung micrometastases, be-cause the critical organ could be the lung itselfinstead of the hematopoietic red marrow [34, 35].The main limitations of this method are reported inTable 1.
The goal of the lesion-based dosimetry(Maxon approach) is to individualize radioiodideactivity that delivers the recommended absorbeddoses to ablate thyroid remnant or to treat meta-static disease while minimizing the risk to thepatient [36]. These absorbed doses are tradition-ally considered to be �300 Gy to ablate thyroidremnant and �80 Gy to successfully treat meta-static disease [36].
In order to determine the activity required todeliver the absorbed doses, it is necessary to mea-sure the uptake, clearance, and concentration of131I contained in the identifiable thyroid remnantsand/or metastases. One way to ascertain theseparameters is through an analysis of selectedregions of interest (ROIs) on conjugate-viewgamma camera images or on SPECT images,obtained at sequential time points after adminis-tration of a tracer activity. Typically, these imagesshould be acquired at 24, 48,72, and 96 h aftertracer administration, but later time samplingmight be necessary if the uptake and clearanceare delayed. In addition, transmission images tocorrect for attenuation in the lesion area, scatterimages, as well as calibration procedures are nec-essary. A curve-fitting procedure is then employedto determine the assumed single-exponential half-life value and to extrapolate the curve to zero time todetermine the initial activity in the lesion [28].
Pre-therapeutic dosimetric assessments of theactivity required to achieve a certain prescribed
Table 1 Problems and difficulties of limited bone marrowdosimetry (Benua approach)
No valid clinical data or outcome rates yet exist on abenefit of the strategy
The approach does not estimate the absorbed dose to thethyroid remnant or metastasis
“Stunning effect” due to diagnostic activity of 131I couldalter lesion biokinetics and the absorbed dose in asubsequent 131I therapy
Increased cost and practical inconvenience
12 M. Salvatori et al.
absorbed dose to a remnant or lesion are oftenbased on adaptations of the generic MIRD equa-tion for absorbed dose, as previously described:
�D ¼A! �S
where �D denotes the mean absorbed dose to theremnant/lesion, Ã is the cumulative activity, andS is the “S factor” of the MIRD scheme dependingon the lesion/remnant mass.
For dosimetry ofmetastases, CT,MRI, or US canbe used for attenuation correction and to determinethe mass, while no thoroughly validated method isyet available for ablative treatments to exactly cal-culate the thyroid remnant volume after surgery.
If the lesions are small, the “nodule module” ofthe OLINDA/EXM software might be useful togenerate a spherical model of the remnant and/ortumor. Furthermore, if the size of the lesion issmaller than 5.0 mm (assuming that such smallsize can actually be accurately determined), thenthe tissue range of the beta particles can no longerbe neglected in the dose calculation. This as wellas other limitations of the lesion-based method isreported in Table 2.
Conventional radiopharmaceuticals that allowquantitation of radioiodide uptake in thyroid rem-nants and metastases, such as 123I-iodide or 131I-iodide, have limitations; in fact, there are prob-lems regarding cost and the logistics of supply for123I-iodide, while 131I-iodide has poor imagingproperties (that translate into relatively low sensi-tivity) and its use can cause the so-called “stun-ning” phenomenon [27]. In contrast, with theintroduction of hybrid positron emission
tomography/computed tomography (PET/CT)devices to the clinic, 124I PET/CT is becomingan emerging and attractive methodology forlesion dosimetry in the management of patientswith DTC [37]. With its ability to determine theconcentration of 124I-iodide at anatomical sites ofinterest, PET/CT provides quantitative imagesand provides higher spatial resolution and imag-ing sensitivity than gamma camera-baseddevices [37].
Using the PET data as input to a fully three-dimensional dose planning program, Sgouros et al.[38] calculated spatial distributions of absorbeddoses, isodose contours, dose–volume histograms,and mean absorbed dose estimates for a total of56 tumors. Themean tumor-absorbed dose for eachpatient ranged widely, from 1.2 to 540 Gy, whiledistribution of values for the absorbed dose inindividual tumor voxels was even more dispersed,ranging from 0.3 to 4,000 Gy.
Median per patient tumor radiation-absorbeddoses between 1.3 and 368 Gy were reported byde Keizer et al. [39], who performed tumor dosim-etry after rhTSH stimulated 131I-iodide treatment.Dosimetric calculations were performed usingtumor radioiodide uptake measurements fromposttreatment 131I scans, while tumor volumeswere estimated from radiological images.
In general, a 124I PET/CT dosimetry protocolinvolves estimating the absorbed dose per admin-istered 131I activity for each radioiodine-positivelesion, allowing the calculation and the choice ofthe actual recommended 131I activity. However,pre-therapeutic 124I PET/CT dosimetry requiresthe knowledge of lesion volumes in order to ade-quately correct for partial volume effects. Sucheffects can reducemeasured activity concentrationsin lesions by up to ~three times the spatial systemresolution, i.e., up to ~2 cm in diameter.
Often no morphological CT correlates can beassigned to 124I PET foci. This can be partiallyattributed to the fact that CT examinations prior toradioiodine therapy need to be performed withoutcontrast media to avoid iodine contamination. Ifno CT correlates exist, the target volumes mustthen be assessed from PET images alone by apply-ing various threshold methods. The original 124IPET dosimetry protocol entailed five PET
Table 2 Problems and difficulties of lesion-based dosim-etry (Maxon approach)
Not uniform absorbed doses within each lesion
An accurate estimate of the lesion mass is not alwayspossible
Low uptake in lesions and, therefore, low count rates maycause statistical errors in the measurements
The biological effectiveness of dosimetry-guided 131Itherapy is not proven yet
“Stunning effect” due to diagnostic activity of 131I couldalter lesion biokinetics and the absorbed dose in asubsequent 131I therapy
Radiobiology and Radiation Dosimetry in Nuclear Medicine 13
measurements at 4, 24, 48, 72, and 96 h after 124Iadministration, although simplified models byusing four, three or two points (24 h/96 h) havebeen proposed [40].
There are only a few published studies that haveexamined the absorbed dose in thyroid remnantsand metastases using 124I PET/CT. Freudenberget al. [41] determined a median LDpA of 95 Gy/GBq for bone metastases (n = 73), 113 Gy/GBqfor lymph node metastases (n = 32), and 86 Gy/GBq (n = 14) for lung metastases in those patientswho were eligible for RIT.
At the moment, considering the slow progres-sion disease and long follow-up period, it is diffi-cult both to evaluate the long-term benefits and todesign classical blinded and randomized studiesin DTC patients submitted to pre-therapy 124IPET/CT dosimetry. However, pre-therapy 124IPET/CT dosimetry seems to be very useful inselected patients with locoregional or distantmetastases who may benefit from radioiodinetherapy with an individually tailored escalatedactivity or to abandon the therapy because ofinsufficient obtainable dose in the lesions.
Besides being a promising method to obtainaccurate dosimetry in patients with metastases,124I PET/CT imaging is a useful diagnostic toolfor accurate pre-radioiodine therapy staging, witha diagnostic accuracy similar to theWBS obtainedafter high therapeutic activities of radioiodine.
Peptide Receptor RadionuclideTherapy
Peptide receptor radionuclide therapy (PRRT)represents a promising option for patients withsomatostatin receptor-expressing tumors. Sev-eral clinical trials have proven its efficacy, espe-cially for neuroendocrine tumors [42, 43].However, possible radiation-induced renal dam-age and large inter-patients’ variability inbiodistribution and tumor uptake require accu-rate dosimetry-based therapy planning. Recentimprovements in dosimetry methods [44–51]and radiobiological models [18, 52, 53] haveresulted in promising results and correlationsthat constitute challenging perspectives for
optimized PRRT and for other radionuclide ther-apies as well [53–57].
90Y-DOTATOC, 90Y-DOTATATE, and 177Lu-DOTATATE are the most widely employed radio-pharmaceuticals for PRRT. Pilot trials also consid-ered 111In-octreotide for therapy, due to the highLET of its Auger-electron emission. However,since tumor response was seldom achieved, 111In-based PRRT protocols have virtually been aban-doned [42].
The physical half-life of 90Y is compatible withthe peptide kinetics, while the high energy of theβ-particles confers high probability of killing allneoplastic cells in a certain volume around theuptake site through the cross-fire effect. Con-versely, 90Y is not easily suitable for imagingdue to the lack of γ-emission, even if promisingresults have been shown for planar and SPECTbremsstrahlung 90Y-images corrected for scatterand detector response, either based on MonteCarlo simulations or obtained by new-generationequipments (SPECT/CT) [58–60]. The possibilityto obtain 90Y-PET images due to the low inci-dence of pair production of 90Y (branching ratioof 32 � 10�6) is also challenging. It has alreadyfound application in the radioembolization ofliver lesions using 90Y-microspheres [61, 62] andhas been recently studied to be applied in90Y-PRRT [63].
111In-octreotide, 86Y-octreotide, and 68Ga-peptides have been proposed as alternativeoptions to 90Y-imaging. Due to their similar chem-ical characteristics, the assumption of comparablebehavior in vivo of 111In- and 90Y-derivatives hasbeen widely accepted [64]. Thus, several authorshave used the identical molecule labeled witheither 111In or 90Y for imaging or for therapy,respectively (e.g., 111In-DOTATOC and 90Y-DOTATOC). Since the physical T1/2 of 111In isalmost identical to that of 90Y and is compatiblewith the distribution kinetics of peptides, the diag-nostic activities usually administered (~185MBq)allow one to obtain serial images (planar, SPECT)over 3–4 days, although some difference in thechemical structure of 111In-octreotide cannot offeridentical biokinetics of the corresponding90Y-conjugate. A fortiori, even less recommend-able is a dosimetry plan based on the distribution
14 M. Salvatori et al.
of 111In-octreotide (Octreoscan#), even thoughsome authors claim its use for a “practical” dosim-etry [65, 66]. The same compound labeled with86Y (86Y-DOTATOC) represents a further option,since it totally preserves the chemical nature of90Y-derivatives and offers PET resolution. How-ever, limitations of this approach are due to thephysical T1/2 of
86Y (14.7 h, too short to followthe kinetics of uptake peptide and retention), com-plex image quantification, cost, and poor availabil-ity [64]. Similarly, 68Ga-peptides are not suitablefor dosimetry purposes, despite the high-qualityPET images provided, because of the extremelyshort T1/2 of 68Ga (68 min) as compared to thekinetic pattern of peptide distribution. Furthermore,the chemical properties of 68Ga might slightly alterthe biodistribution kinetics of the radiolabeled pep-tide as compared to the therapeutic agent [64].
In comparison with 90Y, 177Lu induces lessdamage by cross-fire effect, but releases higherenergy in smaller tissues. Moreover, the γ-raysemitted by 177Lu are suitable for imaging and dosi-metry, although for proper scintigraphic imaging,diagnostic/dosimetric activities of at least of370–740 MBq should be administered. Mostoften dosimetry is evaluated after administeringtherapeutic activities of 177Lu-DOTATATE (i.e.,3.7–7.4 GBq), as treatment is usually given in mul-tiple cycles. So, the activity to be administered incycles after dosimetry can, in case, be adjustedbased on the dosimetry results.
90Y- and 177Lu-peptides have shown similarbiological half-lives for organs and lesions, withvarying uptakes depending on the different ex-pressions of somatostatin receptors with respectto the peptide affinity. The same dosimetry methodsand time schedules for data recording can be usedfor 90Y- and 177Lu-PRRT, but dosimetry must beassessed specifically for every used radiopeptide,and for the single patient, due to wide intra-patientvariations as well as frequent inter-patient differ-ences on tumor uptake.
The absorbed doses per unit activity for 177Lu-peptides are much lower (two- to fourfold) than for90Y-peptides [64]. The activities administered in177Lu- or 90Y-PRRT should vary accordingly,although the therapeutic protocols most commonlyemployed in clinical studies are not yet uniformly
established with respect to activities administeredand number of cycles [67–69].
Table 3 reports a summary of the dosimetricresults for the most commonly used 90Y- and177Lu-peptides (90Y-DOTATOC and 177Lu-DOTATATE), which share some properties:(1) the pharmacokinetics are characterized byvery fast blood clearance and urinary elimination,leading to low exposure of the whole body (Fig. 3);(2) the spleen, kidneys, and liver receive thehighest absorbed doses; (3) the kidneys are thedose-limiting organs; and (4) no significant uptakein bone or red marrow is typically reported.
To reduce renal radiation burden, preclinical andclinical studies showed that the infusion of protec-tive agents (negatively charged amino acids) allows25–65% reduction of the kidney uptake [70].Despite such protection, the cumulative dose tothe kidneys could still be borderline with the limitsconsidered for nephropathy induction, especiallywith 90Y-peptides.
Increased application of PRRT has stimulatedinterest in improving calculation of the radiationburden to organs at risk. There are two remarkablestudies by Sandstrom et al. that focus on individ-ualized kidney and bone marrow dosimetry andon the method dependence, observer variability,
Table 3 Absorbed dose estimates for the principle PRRTtrials with 90Y-DOTATOC and 177Lu-DOTATATE
Absorbed doses per unit activity (Gy/GBq)mean values among patients published bydifferent authors90Y-DOTATOC 177Lu-DOTATATE
Adapted from Cremonesi et al. [64], with permissionaAbsorbed dose values reported include renal protectionbFor tumors, instead of the mean values, the ranges ofvariability are presented
Radiobiology and Radiation Dosimetry in Nuclear Medicine 15
and kidney volumes of dosimetry for 177Lu-PRRT[48, 49]. Some papers use SPECT/CT-based renaldosimetry in 177Lu-PRRT [50, 51], while an accu-rate method for planar image activity quantifica-tion and absorbed dose assessment in general isdescribed by the group of Sjögreen et al. The clin-ical value of the absorbed dose to the kidney is thetopic discussed by Swärd et al. [45].
Two papers compared planar and SPECTimages of 177Lu-PRRT, both considering planarimages corrected for scatter, background, attenu-ation, and response of the system, and SPECTimages corrected for attenuation and response ofthe system. The first, by Garkavij [44], observed~10% difference in the dosimetric results for thekidneys when comparing planar images using twodifferent background corrections, ~20% differ-ence when comparing planar with SPECT images,and ~10% difference when comparing the hybridmethod using SPECT combined to planar imageswith the 3D SPECT method. The second, bySandström [67], obtained a difference within14% for the kidneys when comparing SPECTvs. planar images, while a difference within 10%for kidneys up to 23% for the liver when compar-ing two different 3Dmethods to draw the volumesof interest.
Other comparisons were made by Larssonet al. who focused on different planar dosimetricmethods for the kidneys and studied the
influence of the number of time points and theuse of standard organ sizes. The authors found alarge interindividual variation – which increasedin case of the lack of late acquisition on day 7 –and demonstrated the need of personalized dosim-etry and treatment planning [47]. Guerriero et al.further increased the accuracy of the biokinetics ofkidneys and tumors in both, 177Lu- and 90Y-peptidetherapy. They investigated the most adequatetiming for imaging and interpolation of thetime–activity curve, the performance of a simpli-fied dosimetry by means of only one to two scans,and the influence of renal risk factors and differentpeptides (DOTATOC vs. DOTATATE) [71]. Thetrapezoidal method followed by physical or biolog-ical decay after experimental data was comparedwith mono- and bi-exponential fits, skipping or notthe 6 h and the 3-day time points. The authorsfound that data should be collected at least up to~100 h for 177Lu therapy and ~70 h for 90Y therapyin order to minimize dose uncertainties.
Another important issue for biokinetics is thepossible variation among cycles. The study byGarkavij et al. compared dosimetry to the samepatients in different cycles and showed that thefirst two of the four planned therapy cycles makethe major contribution to the tumor-absorbed dose,possibly due to a saturation of the peptide receptors,while the different cycles contribute on averageequally, within 10%, to the absorbed dose to the
kidneys [44]. These findings apply in general andhave been confirmed by other investigations [57],but there is a minority of cases in which the tumor isso avid of radiopeptides that it sequesters a veryhigh percentage of the injected activity, leading to aso-called sink effect that decreases the activity con-centration in healthy organs including the kidneys.In such cases, if the tumor is responsive during thecourse of therapy, the biokinetics in subsequentcycles may vary consistently, and dosimetry at acertain cycle is no more representative of the othercycles and not useful to estimate the cumulativedoses to organs at risk and tumor [72].
In the attempt to improve accuracy of renaldosimetry estimates, the standard methods thatassume uniform activity distribution in kidneyshave been shifted to the multi-region MIRDmodel for a sub-organ kidney dosimetry anddose-rate effects [22, 55, 73, 74]. Some authorsproposed the analysis of SPECT images to assignactivity to the cortex or to the medulla for apatient-specific dosimetry [66]. In truth, the reso-lution of SPECT images is unable to provide areliable activity distribution within the kidneysubstructures, being too low as compared to the1–3 mm thickness of the cortex, for instance.More detailed information on intrarenal distribu-tion has been derived instead from experimentalresults of renal autoradiograms [75].
The impact of the physical characteristics of theradionuclides with respect to inhomogeneous activ-ity distribution (also within sub-organ regions) isa further issue concerning potential nephrotoxicity[69]. A threshold biologically effective dose (BED)of 33 Gy for kidney radiation damage and a BED50(defined as the BED value derived from the TD50value derived from the EBRT) of 44Gywere foundfor 90Y-PRRT [55]. Besides the most relevantimpact on PRRT, these findings have shown thegreat potential of sharing information from differentradiation releasemodalities. As a further support forthe radiobiological model, clinical experience hasshown thatmultiple-cycle protocols lower the neph-rotoxicity, while patients with higher BED valuesand more serious side effects to the kidneysreceived the treatment in a few cycles [69, 76, 77].This observation perfectly matches with the theo-retical expectation from the BED concept: for a
given cumulative dose, the higher the number ofcycles, the lower the total BED, thus the lower thedamage [69, 78]. Clinical results on 90Y-PRRT haveprovided evidence of the safety up to a BED ofabout 40 Gy to the kidneys, cumulatively, and thatrisk factors (such as hypertension and diabetes)lower the tolerability to a BED of about 28 Gy[55, 76].
Treatment protocols based on multiple therapycycles represent a useful modality to lower toxic-ity for a same cumulative activity, and/or improvethe therapeutic outcome for a same fixed BED tothe kidneys, owing to the different radiosensitivityof most tumors versus the kidney tissue. Cyclesseemed especially effective in 90Y-PRRT, wherefrequent occurrence of renal impairment has beenclinically confirmed [69, 76, 79].
90Y-peptides appear to be less nephrotoxic [43,80, 81]. Possible reasons for these different out-comes are the different particle ranges in tissuesand different peptide localizations. The short-rangeβ-particles of 177Lu-peptides, or the Auger elec-trons of 177Lu-peptides, might irradiate the tubuli(radioresistant cells) more selectively while thelong-range β-particles of 90Y-peptides may incre-ase the irradiation of the more radiosensitive glo-meruli, with consequent higher toxicity [69, 75,78]. On the other hand, the advantage of cyclingPRRTwith 177Lu is not as important with 90Y. Thisis clear when considering that the contribution tothe cumulative absorbed dose to the tumor aftereach therapy cycle gradually decreases [44] andthat the absorbed dose to the kidneys with 177Lu-PRRT is much lower at the activities usuallyadministered in clinical trials, leading to a lowerrisk of nephrotoxicity. Overall, the use of too manycycles is not recommendable for 177Lu-PRRT,while four cycles or possibly less seem to offer abetter chance to avoid repair of sublethal cell dam-age and repopulation without dramatically alter therenal risks.
Despite long-term data analysis of 90Y-trialsand 177Lu-trials, the intrinsic toxicity of the tworadiopeptides is still to uncertain [64, 77, 82, 83].Because the 177Lu-based and the 90Y-based clinicalprotocols use fixed total activities (e.g., 177Lu, fourcycles of 7.4 GBq; 90Y, three cycles of 3.7 GBq)that lead to lower kidney absorbed dose and BED
Radiobiology and Radiation Dosimetry in Nuclear Medicine 17
values for 177Lu-schemes as compared with 90Y.A reliable comparison of 177Lu- vs. 90Y-peptidetherapy would require randomized trials conceivedto release the same absorbed dose or BED usingdifferent radiopeptides. The choice of the mostsuitable radiopharmaceutical can be made basedon individual differences in tumor mass and loca-tion, adjacent tissues, and targeting compoundaffinity. In principle, the physical characteristicsof 177Lu, with lower tissue penetration, make itmore suitable for small tumors and micro-metastases, while the cross-fire effect 90Y mighthave the advantage of a higher radiation burdento larger lesions [64]. This hypothesis has beensupported by preclinical findings and is the basisfor new clinical rationales proposing cocktails of177Lu- and 90Y-radiopeptides. New interestingapproaches propose tandem treatments with 90Y-and 177Lu-peptides, with equal or different admin-istered activities of the two radiopharmaceuticals[84, 85].
For tumor response, a first remarkable correla-tion has been observed between tumor-absorbeddose and tumor reduction with 90Y-DOTATOC[65]. Responding tumors could be identified asthose receiving much higher doses compared tononresponding (up to sixfold, ~230 vs. ~40 Gy).Moreover, when correlating tumor-absorbed doseversus lesion mass reduction, a trend versus adose–effect relationship was found, although notstatistically significant, with a correlation coeffi-cient of 0.5.
Excellent correlations were obtained betweenabsorbed doses and tumor volume reduction after177Lu therapy, with a correlation coefficient of 0.6for tumors bigger than 2.2 cm and a correlationcoefficient of 0.9 in tumors bigger than 4 cm.These results were obtained by the improvementof dosimetry methods, namely, by correcting forthe partial volume of the lesions identified inSPECT images [57].
Many parameters may influence the responseof tumors – such as tumor dimension, vasculari-zation, radiosensitivity, and activity distribution.Larger series of data with specific radiobiologicalparameters for different tumor characteristics areto be collected and will certainly improve out-come prediction.
Studies have measured circulating NET tumortranscripts (NETest), based on several markergenes to monitor tumor gene activity levels. Theresults confirmed that this test provides assessmentof disease status and treatment effectiveness withsignificantly higher accuracy and earlier time pointsas compared with other biomarkers (such ascromogranine A) and morphological/functionalimaging [86, 87]. It is quite clear that interdisciplin-arity including dosimetry and genetic profile willplay a crucial role in radionuclide therapies, allo-wing identification of patients that are not likely tobe responsive and/or patients with a low risk ofadverse sequelae, guiding trials, and tailoringtherapies.
Radioimmunotherapy of Lymphoma
Radioimmunotherapy (RIT) offers an importantoption for the treatment of follicular low-gradenon-Hodgkin’s lymphoma (NHL) refractory orrelapsed after treatment with the current best prac-tice [88]. Two radiolabeled antibodies are com-mercially available for treatment, tositumomaband ibritumomab, that are the radiolabeled immu-noglobulin components of Bexxar and Zevalin,respectively [88, 89].
Bexxar is the 131I-labeled anti-CD20 antibodytositumomab, while Zevalin is the 90Y-labeledanti-CD20 antibody ibritumomab. Althoughboth tositumomab and ibritumomab recognizethe same epitope CD20 (one of many epitopesexpressed on the mature B cell), they have slightlydifferent binding characteristics [88].
For both radiopharmaceuticals, an unlabeledantibody is infused before administration of theradiolabeled murine anti-CD20 antibody compo-nent. In the Bexxar regimen, both the labeled andunlabeled antibody are tositumomab. In theZevalin regimen, the unlabeled antibody isrituximab (the chimeric antibody used as animmunotherapeutic and marketed as Rituxan),while the labeled antibody is ibritumomab [88,89].
In Europe only Zevalin is commercially avail-able, while in the USA and Canada, both ZevalinandBexxar have been approved for clinical use [88].
18 M. Salvatori et al.
No direct comparison in a randomized blindedtrial has been performed to assess whether thedifference in physical characteristics of the tworadionuclides, 131I and 90Y, have different thera-peutic effects or toxicity.
In principle, the greater energy of the β emittedby 90Y is thought to be advantageous in the ther-apy of larger tumor masses, whereas the lowerenergy of the 131I-particle emission is thought tobe an advantage for treating patients with smalltumor foci and marrow involvement. In thenon-myeloablative setting, the use of eitheragent is contraindicated for patients with lympho-matous infiltration exceeding 25% of the bonemarrow [90].
For Bexxar and Zevalin, different protocolsand dose determinations have been reported, alsodue to the different approval requirements by reg-ulatory agencies in the USA and Europe. How-ever, for both radiopharmaceuticals, the red bonemarrow is the dose-limiting organ due to its intrin-sic radiosensitivity, to the rapid equilibration ofthe radiolabeled antibodies within its extracellularfluid volume, and to the long retention kinetics inthe bone marrow [88].
When using Bexxar, dosimetry is estimated todetermine the whole-body radiation-absorbed dose,since hematological toxicity and the dose–clinicalresponse relationship depend on the whole-bodyradiation-absorbed dose rather than on a MBq/kgdosing schedule [91].
The optimal clinical benefit with acceptablehematological toxicity has been observed at 65–75-cGy whole-body radiation-absorbed dose, consider-ing 65 cGy for patients with platelet counts between100,000 and 150,000 and 75 cGy for patients withplatelet counts greater than 150,000 [88].
The whole-body radiation-absorbed dose isdetermined from three WBS acquisitions after theadministration of 185 MBq of 131I-tositumomab(with prior infusion of 450 mg of unlabeled tosi-tumomab), administered for determining the resi-dence time which is necessary for dosimetricestimates.
The purpose of the scan is simply to evaluatethe whole-body total counts rather than to producea diagnostic image, because the parametersinvolved in visualizing a tumor (dose
administered, tumor size, and location) are differ-ent from those involved in radiobiologicalresponse evaluations [88].
Whole-body counts are determined from thetotal counts on the anterior and posterior WBSacquired 1 h postinjection (day 0), then 2 days(day 2) and 5 days (day 5) later, to determine theradiopharmaceutical residence time (τ) and cumu-lated activity (Ã) in the body.
To calculate the desired therapeutic activity,the following equation can be used:
Theraputicdose ¼ A!
τ
DesiredTBD cGyð Þ75cGY
The calculation simply divides a cumulatedactivity, Ã (tabulated for several patient’s weight),that would result in the patient receiving a 75-cGywhole-body radiation-absorbed dose, by the patient-specific residence time, τ. This would result in theactivity associated to a 75-cGy whole-body ab-sorbed dose that could be also rescaled by anabsorbed dose ratio if a value of total-body absorbed(TBD) dose different from 75 cGy is desired.
Seven to 9 days after the initial “dosimetric”study, the infusion sequence (unlabeled tosi-tumomab followed by 131I-tositumomab) is re-peated with the 131I-tositumomab therapeuticactivity (1.85–5.5 GBq) that had been determinedby dosimetry (Table 4).
Table 4 Organ radiation absorbed doses (mGy/MBq) for90Y-ibritumomab tiuxetan (Zevalin®), based onpre-therapeutic 111In imaging
OrganNumber ofpatients
Median and range(mGy/MBq)
Spleen 166 7.35 (0.37–29.7)
Liver 179 4.32 (0.85–17.5)
Lungs 179 2.05 (0.59–4.86)
Red marrow(blood derived)
179 0.59 (0.09–1.84)
Red marrow(sacrum derived)
179 0.97
Kidneys 179 0.22 (0–0.95)
Bone surfaces 179 0.53 (0.09–1.31)
Urinary bladderwall
179 0.89 (0.38–2.32)
Other organs 179 0.41 (0.06–0.62)
Total body 179 0.54 (0.27–0.78)
Radiobiology and Radiation Dosimetry in Nuclear Medicine 19
In the USA and EU countries, biodistributionstudies are not required because of the lack ofcorrelation between red marrow dose and toxicityand considering that red marrow toxicity is revers-ible. This choice (which seems to be dictatedmainly by practical/economical reasons) is argu-able, as cases in which only the scintigraphicimages were able to predict toxicity of the treat-ment are not so rare [92]. However, when usinglarger activities in clinical trials involving myelo-ablative doses with stem cell transplantation, per-sonalized dosimetry estimates are required to avoidunpredictable toxicity. In fact, with bone marrowrescue, it is not possible to identify a priori a “safe”maximal activity or a unique critical organ for allpatients, because of the wide intra-patient variabil-ity in doses to the vital organs.
At present, neither 90Y-ibritumomab tiuxetandosimetry outcomes in favor of its predictivityhave been found nor correlation between red mar-row dose and hematological toxicity has beendemonstrated [91, 93–96]. This considerationhas discouraged the practice of red marrowdosimetry for Zevalin. In this regard, toxicity inthese patients is most likely linked to involvementof bone marrow by the disease and to reducedbone marrow reserve due to previous aggressivechemotherapy regimens [97].
The therapeutic activity of Zevalin for thenon-myeloablative therapy of rituximab-refractoryor relapsed patients with low-grade follicular non-Hodgkin’s lymphoma is prescribed proportionallyto the patient’s weight, with recommended admin-istered activity of 15 MBq/kg up to a maximumlimit of 1,200 MBq [94]. Patients with plateletcounts between 100,000 and 150,000 shouldreceive 11 MBq/kg [94]. Much higher activities,ranging from 29 to 55 MBq/kg, have been usedunder myeloablative regimens, followed by autol-ogous stem cell transplantation (ASCT) [98].
Radioembolization of Liver Tumors
Trans-arterial radioembolization (TARE) is a loco-regional treatment developed in order to releasehigh radiation doses to malignant hepatic lesionsby intra-arterial administration of a radiation
vehicle. The rationale is the same as for trans-arterial chemoembolization (TACE): liver tumorsaremainly fed by arterial blood, while normal tissueby portal blood. TARE consists of the intra-arterialadministration of a radioactive agent. This is per-manently trapped in the microcapillaries where itdelivers its radiation until complete physical decay.In the last decade, significant response rates havebeen achieved with this approach in patients withunresectable primary hepatocarcinoma (HCC) [99]or secondary hepatic malignancies [100].
Several techniques have been tested in researchtrials, including the administration of radiolabeledmolecules (such as 90Y-,131I-,188Re-,166Ho-Lipiodol) or of microspheres loaded with radionu-clides (e.g., 90Y, 166Ho), differing in size, material,and specific radioactivity. However, the impressiveincrease in the number of treated patients in the lastdecade follows the registration of only two medicaldevices, i.e., microspheres loaded with 90Y: (1)SIR-Spheres made in plastic resin (Sirtex Medical,Lane Cove, Australia) and (2) TheraSpheremade inglass (MDS Nordion, Ottawa, Canada). The maindifference between the two products is the numberof administered particles, which is ten times higherfor resin particles. This implies a truly embolicbehavior, never observed in glass microspheres.The second difference is the approved indicationin the USA versus Europe. The FDA approved theuse of resin spheres in patients with colorectal car-cinomametastatic to the liver, while glass spheres inHCC patients with or without portal vein thrombo-sis. In Europe and in various countries worldwide,both agents have regulatory approval for liverneoplasia.
The amount of activity to be administeredshould generally be established taking into ac-count the clinical and dosimetric factors whichaffect the outcome: basal liver function (Child-Pugh score, presence of portal vein thrombosis,previous or concomitant treatment), tumor bur-den, targeted organ fraction, predicted absorbeddose to normal tissue, and absorbed dose tolesions. Actually in Europe, the Council Direc-tive 2013/59 in Article 56 prescribes that anyradiation treatment be optimized using dosime-try. In practice, the choice of the injected activityhas been based on empirical approaches or on
20 M. Salvatori et al.
rough dosimetric evaluations, as summarizedhereinafter.
For both devices, therapy is generally simulatedby intra-arterially administered 99mTc-albuminmacroaggregates (99mTc-MAA), in order to evalu-ate possible shunting to the lungs (lung shunt frac-tion, LSF), which limits the administrable activity,or avoid gastrointestinal (GI) shunt, which is anabsolute contraindication to treatment. A planartrunk scintigram and a liver SPECTscan are usuallyaccomplished. A major advantage deriving fromthe permanent trapping is that, differently from allother radiopharmaceuticals, images can be quanti-tatively analyzed to perform dosimetric evaluationthough taken at only one time point. The adequacyof 99mTc-MAA for simulation is under discussion.Although similar distribution patterns of 99mTc-MAA and bremsstrahlung 90Y-microsphere imageshave been generally reported, some dissimilaritieshave also been observed, possibly due to the dif-ferent size and number of MAA versus micro-spheres or to occasional alterations of the originalvascular anatomy produced by angiography [101].Nevertheless, the acquisition of pre-therapeuticimages represents a suitable source of clinical anddosimetric information for risk/benefit evaluation,through a treatment planning session similar to thatordinarily performed in external beam radiother-apy. Post-therapy images can be obtained either asbremsstrahlung SPECT or as 90Y-PET. The latterare by far more accurate from the quantitative pointof view. Post-therapy imaging has almost the samelevel of importance as the 99mTc-MAA scan, sinceit demonstrates the real therapeutic biodistribution.
Patient-specific dosimetry requires a detailedslice-by-slice volume of interest (VOI) drawingaround tumor (T) and non-tumor tissue (NT).Using the mean dose approach, values of theabsorbed doses per unit activity can easily bederived from two simple equations. The first is theway to convert counts in the image in 90Yactivity:
AVOI90Y� �
: Atotal 90Yð Þ ¼ VOIcounts : totalcounts
D Gy½ � ¼ 50 � AVOI90Y½ �
MVOI kg½ �
Amore sophisticated evaluation can bemade bythe voxel dosimetry approach or by Monte Carlo
modeling that provides information on dose distri-bution and expected radiobiologic effects at thevoxel level [102].
Producers indicate different approaches tochoose the amount of activity to be injected forthe two radiopharmaceuticals [101]. Three mainmethods are suggested [101] for resin spheres: theempirical method, the body surface area (BSA)-based method, and the partition method.
The empirical method does not personalize thetreatment for different liver dimensions or tumoravidity, but it takes into account the tumor in-volvement and attempts to lower the radiationrisks to the lungs and the NT tissues. With this,method activities range from 1.2 to 3.0 GBq, andthe doses received by the lungs and by the NT arewithin 18 and 83 Gy, at most. According to Ken-nedy et al. [100]. “The Radio Induced Liver Dis-ease (RILD) was diagnosed in 28 of680 treatments (4%), with 21 of 28 cases (75%)from one center, which used the empiric method.”
The BSA method, probably the most widelyemployed for resinmicrospheres, has been proposedsince in normal patients, liver mass correlates withBSA. The basic equation, empirical, includes thepatient body surface area: BSA m2ð Þ ¼ 0:20247½ �H0:725�W 0:425, withH ¼ height mð ÞandW ¼weight kgð Þ� and provides a maximum activity sup-posed to be safe for NTand lungs, once applying thesame restrictions for lung shunt as above:
A ¼ BSA� 0:2ð Þ þ MT
MT þML
where A = activity (GBq),MT = tumor mass, andML (g) = total liver mass. In general, the activitiescalculated by the BSA method are more conserva-tive than those derived from the empiric method,never exceeding 2.5 GBq. Although includingsome individual parameters, the reliability of thismethod in terms of tailored evaluation should notbe overemphasized. In fact, direct measurements inpatients have provided evidence that the BSA-based estimates do not correlate with liver massnor with tumor involvement. Comparison betweenthe BSA-based and the dosimetry methods showeddiscrepancies in activities to be administered rang-ing from �30% to 35% [103].
Radiobiology and Radiation Dosimetry in Nuclear Medicine 21
In the partition method [104], the activity to beadministered is calculated within the MIRD equa-tions, once a limit dose is prescribed for NT; lungsafety is also considered. Liver involvement,tumor avidity as compared to the NTL, and thepossible occurrence of lung shunt are taken intoaccount by the following equation:
A ¼ DnL ¼ AT �MnL þ AL �MnL
49, 670� AL 1� LSFð Þ
where A = activity, DnL(Gy) = absorbed dose(Gy) limit for NTL, A = tumor activity (GBq),A = liver activity (GBq), M (g) = NTL mass,and LSF = lung counts/(lung + liver counts).
Although this model was originally designedfor single or discrete nodules, appropriate modifi-cation by a weighted T/NT ratio makes it easilyapplicable also to multiple lesions [105]. The re-view paper by Cremonesi et al. [101] provides theabsorbed dose limits applied by several authors,including the most common recommendations[106] and more conservative approaches [105].
The model proposed for RE with glass spheresrelies on a simplified dosimetry equation, in whichthe dose averaged on the injected liver (DL) isprescribed:
A ¼ DL � VL � 1:03
50 1� LSFð Þ
where A = activity, DL(Gy) = prescribed liverdose, VL = total liver volume, and LSF = lungshunt fraction.
Absorbed doses to tumor and NT are not sep-arately calculated, so no distinction is made fordifferent tumor involvement or uptake ratios. Sev-eral studies [106] have indicated prescribed radi-ation doses (DL) of at least 100 Gy for a maximaleffect on tumors, based on the fact that no dose-limiting organ toxicity has been observed inpatients who had received nominal absorbeddoses of up to 150 Gy. Mean cumulative dosesto the treated liver as high as 200 Gy or even390 Gy have been described as tolerated in pa-tients affected by HCC with Okuda stage II andstage I who received multiple treatments [107].Overall, these doses are apparently quite far from
the limits recommended in the 90Y-resin approachesand much farther than the tolerance doses set byexternal beam radiotherapy (30–35 Gy) to avoidexcessive risk of radiation hepatitis [105]. This isexplained with the nonuniformity of absorbed dosedeposition at the microscopic level, which is mark-edly higher for the less numerous glass micro-spheres [108]. Another basic point is the usuallydifferent administration technique. From the USexperience following the split registration, glassspheres against HCC have been injected lobarly,while resin spheres against metastases were admin-istered in the common hepatic artery. These are twocompletely different situations, since the lobarapproach exploits the organ reserve and the regen-eration capability of the liver [109].
The possibility of performing a real treatmentplanning in radioembolization is emphasized bythe result of three studies, which applied radiobi-ological models to analyze response and toxicityafter standard administration of microspheres.Strigari et al. [110] derived the normal tissuecomplication probability (NTCP) and tumor controlprobability (TCP) for HCC treated with resinspheres using post-therapy bremsstrahlung SPECT.TCP (50%) was at 150 Gy, while a dose above200 Gy demonstrated response in all cases. Livertoxicity higher than G2 had a NTCP (50%) valueof 52 Gy. Flamen et al. [111] found a good tech-netium MAA dose – FDG response correlation incolorectal metastases treated with resin spheres.Chiesa et al. [112] determined retrospectivelywith 99mTc-MAA SPECT the NTCP curve forChild A patients treated lobarly with glass micro-spheres, with a risk of radioinduced liver decom-pensation at 70 Gy if averaged over the wholenon-tumoral parenchyma, including the non-injected lobe. This mean inclusive on the non-treated tissue is the simplest way to include thewell-known liver volume effect (the smaller theirradiated fraction, the higher the tolerance). TCPwas dramatically dependent upon the lesion size,being TCP (50%) = 250 Gy for masses less than10 g and around 1,300 Gy for larger tumors. Garinet al. [113] were able to demonstrate a correlationbetween lesion absorbed dose and overall survivalin HCC patient treated with glass spheres, with acutoff of 205 Gy. Compared to Chiesa et al.’s
22 M. Salvatori et al.
results, this means that glass spheres require at least205 Gy to stabilize the disease, while objectiveresponse requires higher dose. Individualizeddosimetry-based administrations with increase ofadministered activity with respect to the producerindication were also safe and successful [114]. Theunexplored way toward treatment planning inradionuclide treatment is open, thanks to dosimetryin radioembolization, which is the less demandingand that with higher impact among all kinds ofradiopharmaceutical type of dosimetry. As a con-firmation, for the first time in the history of nuclearmedicine therapy, both 90Y-microsphere producersmade investment in multicenter research aboutdosimetry [62].
Therapy of NeuroendocrineMalignancy
In the late 1980s, 131I-meta-iodobenzylguanidine(131I-MIBG) was used as a radiotherapeutic meta-bolic agent in neuroectodermal tumors, i.e., thosetumors derived from the primitive neural crest(which develops to form the sympathetic nervoussystem). Malignant neuroectodermal tumorsinclude pheochromocytoma, paraganglioma, car-cinoid tumors, medullary thyroid cancer, andneuroblastoma.
As an analog of noradrenaline, at low concen-trations 131I-MIBG is taken up into cells ofneuroectodermal origin by the noradrenaline trans-porter (NAT). Once internalized, it is stored inintracellular storage granules. Transfer of MIBGfrom the cytoplasm into neurosecretory granules ismediated by an ATPase-dependent proton pump,and MIBG is not metabolized but excretedunchanged [115].
Treatment with 131I-MIBG is indicated fortumors showing adequate uptake and retentionof radiolabeled MIBG on the basis of a pre-therapy diagnostic scan, which is performedusing 123I-MIBG in children and either 123I-MIBG or 131I-MIBG in adults [116].
Most treatments regard neuroblastoma, themost common extracranial solid tumor affectingchildren (approximately 1 per 10,000 live births),most of the cases being diagnosed before the age
of 4. Most of these malignancies originate in thenervous system, although about two-thirds of thecases arise in the abdomen near the adrenalglands. Distant metastases at diagnosis are fre-quent, and treatment of high-risk neuroblastomaincludes surgery, chemotherapy, and 131I-MIBG[117].
In high-stage neuroblastoma, treatment with131I-MIBG may be either palliative therapy, first-line therapy as a single agent or combined withchemotherapy, or consolidation therapy afterinduction of partial remission. More recently, thistreatment has been used as second-line therapy afterfailed induction chemotherapy, combined withtopotecan and stem cell rescue in children withmetastatic neuroblastoma or with myeloablativechemotherapy and autologous stem cell transplan-tation in refractory neuroblastoma [118].
In addition to uptake in the tumor, 131I-MIBGaccumulates in the liver, heart, lungs, and adrenalglands, while the bladder is irradiated by theurine-excreted metabolites of 131I-MIBG. Thy-roid uptake of free radioiodide is preventedusing oral stable iodine. Since many drugs caninterfere with MIBG uptake and storage, thesedrugs should be withdrawn for adequate periodsbefore treatment, and patients should be stabilizedon alternative medication.
High-specific activity (up to 1.48 GBq/mg) isrecommended for therapy, and single-administeredactivities range between 3.7 and 11.2 GBq, ac-cording to tumor burden or local legislation.Since several cycles of therapy with 131I-MIBGmay be required to achieve objective response,these treatments are often repeated at widely dif-ferent intervals, depending on blood count recov-ery; treatment is continued until the maximumclinical response is achieved.
Red bone marrow is the dose-limiting organfor 131I-MIBG therapy, and activity reductionshould be considered in patients with myelosup-pression or with impaired renal function. In pa-tients with neuroblastoma who had received priorintensive chemotherapy, the dose-limiting toxicityof 131I-MIBG therapy is myelotoxicity at 2-Gywhole-body dose, according to thepre-therapeutic 131I-MIBG scans. This thresholdcan be circumvented if bone marrow stem cell
Radiobiology and Radiation Dosimetry in Nuclear Medicine 23
support is available. A total of 4.0-Gy whole-bodydose with stem cell rescue has been given withgood tolerance and no other short-term, dose-lim-iting organ toxicity [119].
The approach to administer fixed activity“fractions” of 3.7–11.1 GBq offers the advantagesof simplicity and shorter isolation and hospitali-zation period required for radioprotection; thisfeature in non-negligible when treating very sickchildren with poor prognosis.
Administration of high activities of 131I-MIBGbased on body weight (555–777 MBq/kg), withstem cell support if necessary, has also been re-ported. A maximum tolerated activity of 444MBq/kg is reported, combined with myeloablative che-motherapy and autologous stem cell transplanta-tion [120].
However, when using fixed activities, nodose–response assessment or optimization on thebasis of absorbed radiation dose is possible. Fur-thermore, the relatively LDR of radiation com-pared with (ultra)high doses may be viewed asradiobiologically suboptimal.
The results obtained overmore than two decadesdemonstrate that whole-body absorbed doses cor-relate both with administered 131I-MIBG activityand with the subsequent development of hemato-logical toxicity [121, 122].
An administered activity of 444–666 MBq/kgof 131I-MIBG may deliver 50–700 cGy of whole-body absorbed dose; 80% of patients withadvanced chemorefractory stage III/IV neuroblas-toma can develop grade 3 or 4 hematotoxicity at awhole-body absorbed dose of 2.5 Gy establishedfrom a pre-therapy 131I-MIBG scan.
In relapsed or refractory neuroblastoma, thewhole-body absorbed dose calculated according tothe standardMIRD schema can be prescribed accu-rately and allows higher activities of 131I-MIBG tobe administered within the safety limits for bonemarrow toxicity [123].
The mean absorbed dose, D, is given by theproduct of the cumulated activity and the MIRDwhole-body-to-whole-body S value, that is[124]:
�D WB WBð Þ ¼A! �S WB WBð Þ
Value S(WB WB) is often obtained using thefollowing equation (correction for body weight):
S WB WBð Þ ¼ 1:34� 10�4m�0:921p
where mP is the patient’s mass in kilograms. Thisequation was generated by interpolating the S(WB WB)values from the MIRD phantoms for anewborn as well as for 1-year, 5-year, 10-year, and15-year-old children, and finally for an adult, eachof which has a specific mass. Table 5 reports theabsorbed doses to the organs calculated for unit of131I-MIBG activity administered.
An experimental MIBG protocol has been pro-posed in which the aim was to deliver a totalwhole-body absorbed dose of 4.0 Gy in two frac-tions, in combination with topotecan, after failureof induction chemotherapy [125]. Post-therapydosimetry is performed after a first fixed fractionof 444 MBq/kg, with calculation of the activitydose to be administered with the subsequent sec-ond fraction in order to achieve the desired totalwhole-body absorbed dose of 4 Gy [126].
Recent studies analyzed the whole-body radia-tion dose (WBD) and tumor-absorbed doses from131I-MIBG therapy in relation to tumor responseand toxicities. Trieu et al. [127] retrospectivelyevaluated a cohort including 213 patients withhigh-risk neuroblastoma treated with 131I-MIBGbetween 1996 and 2015 to correlate WBD from131I-MIBG with tumor response, toxicities, andother clinical factors. The WBD was calculatedfor every patient using radiation exposure rate mea-surements obtained by a ceiling-mounted ioniza-tion chamber or by a handheld ionization chamber.They found that WBD correlated with 131I-MIBGactivity, particularly with 131I-MIBG administeredper kilogram suggesting that activity prescriptionsfor 131I-MIBG therapies should be made based onpatient weight as opposed to a predetermined totalactivity dose in order to achieve a targetedWBD.Arecent study by Minguez et al. proposed an equa-tion, which describes whole-body absorbed doseper unit of administered activity as a function ofpatient mass, as an alternative for prescriptions ofactivity on first administration when dosimetrydata for the individual patient are unknown [128].
24 M. Salvatori et al.
However, Trieu et al. [127] found no relationshipbetweenWBD and overall response, and they wereunable to establish any relationship between hema-tologic or thyroid toxicity and WBD. This unex-pected finding prompts future studies to evaluatetumor dosimetry, rather than just WBD, as a toolfor predicting response following therapy with131I-MIBG.
A study like this has been made by Georgeet al. [129] who evaluated the response, toxicity,and long-term outcome of 131I-MIBG therapy inthe treatment of refractory or relapsed neuroblas-toma following a dosimetry-based 3D individual-ized approach performed in 8 of the 25 patients.
To calculate tumor-absorbed doses, image datawere obtained by 38 SPECT acquisitions per-formed on consecutive days following the treat-ment. Reconstructed SPECT scans for eachpatient were sequentially coregistered to allow 3Dvoxelized dosimetry to be performed using anin-house dosimetry software package (Qrius). Theimage-based 3D dosimetry application providedan absorbed dose map of consecutive therapiesfrom which dose–volume histograms (DVH) werederived.
To date, there is no clearly defined methodol-ogy to incorporate DVHs in patient-specific plan-ning or to compare DVHs for individual therapiesor to relate to outcome. However, it is clear thatdose heterogeneity could affect the outcome ofsubsequent therapies and may partially explainthe variation in responses. In light of this, a 3Ddosimetry approach where DVHs are takentogether with tumor-absorbed dose as well as
dose-limiting criteria provides a reasonablemethodto help plan patient-specific treatment and shouldbe used as a guideline to inform subsequenttherapies.
A dosimetry-based approach on the basis ofpatient pharmacokinetics may often result in theadministration of higher activities with excellentresponse rates while keeping toxicity within ac-ceptable limits. However, to date, there are cur-rently no published randomized controlled trialsof 131I-MIBG therapy for neuroblastoma at anystage of treatment [21]. To maximize the thera-peutic potential of 131I-MIBG therapy and todetermine its place within the patient pathway,well-designed clinical trials incorporating dosim-etry are needed.
Future studies, including more accurate tumordosimetry such as 124I-MIBG with PET/CT tech-nology, could improve the assessment of the rela-tionship between WBD, tumor-absorbed doses,and overall response [130, 131]. Seo et al. [130]estimated expected radiation dose in tumors from131I-MIBG therapy using 124I-MIBG micro-PET/CT imaging data in a murine xenograft model ofneuroblastoma transduced to express high levelsof the human norepinephrine transporter. Thethree-dimensional tool used for estimating the radi-ation dose that evaluated a range of activity of52.8–206 MBq could deliver about 20 Gy totumors.
Patient-specific dosimetry, using quantitative124I-MIBG PET/CT with a GEometry ANd Track-ing 4 (Geant4)-based Monte Carlo method, wasused by Huang et al. [131] in a 10-year-old girl
Table 5 Median and range organs absorbed doses values (Gy) for 131I-MIBG, per unit of activity administered (MBq/kg)
Radiobiology and Radiation Dosimetry in Nuclear Medicine 25
with relapsed neuroblastoma. Organ-absorbed dosefor the salivary glands was 98.0 Gy, heart wall36.5 Gy, and liver 34.3 Gy, while tumor-absorbeddose ranged from 143.9 to 1,641.3 Gy in differentsites.
Finally, the use of 124I-MIBG PET/magneticresonance imaging (MRI), performed with anintegrated PET/MRI system, could be a promisingtechnique in dosimetry as it improves tumor delin-eation because of the high soft tissue contrast inMRI. In a case reported by Hartung-Knemeyeret al. [132], PET/MRI allowed a more accuratevolumetry in comparison to PET/CT, resulting ina reduction of the calculated lesion dose inabdominal muscle lesions up to 70%.
Treatment of Metastatic Bone Pain
Bone pain due to osseous metastases constitutesthe most frequent type of pain among all cancerpatients, with different prevalence among the var-ious types of cancers. In general, oncologicalpractice, breast and prostate cancers are responsi-ble for more than 80% of the cases with bonemetastases [133].
The pathophysiology is not well understood,and multiple mechanisms are postulated, includ-ing tumor-induced cytokines, stimulating factorsreleased by tumor cells, direct nerve injury, andinfiltration of the bone trabeculae and matrix bytumor cells causing osteolysis [134]. The appro-priate management of painful skeletal metastasisincludes the use of systemic analgesics, hormones,chemotherapeutic agents, steroids, external beamradiation therapy (EBRT), radiofrequency ablation,local surgery, and radiopharmaceuticals.
Curative options for multiple skeletal metasta-ses unfortunately, do not exist, and most of thedescribed treatments are palliative [133]. Sys-temic RNT has shown its value in the managementof painful bone metastasis in clinical practice,although it remains an infrequently used treatmentmodality for many physicians, even those workingin the fields of oncology and nuclear medicine[133, 135].
Phosphorus-32 (32P-ortophosphate) andstrontium-89 (89Sr-chloride) were the first bone-
seeking radiopharmaceuticals approved for thetreatment of painful bone metastases [136], whilebisphosphonates labeled with either 153Sm [137],186Re [138], or 188Re [139] are newer among thetraditional bone-seeking radionuclides [140].
Although there are some differences in thephysical half-life, beta energy, penetration range,and biochemical characteristics among the vari-ous bone-seeking radiopharmaceuticals, no clearadvantage in terms of increased response rate hasemerged. A uniform response rate of approximately70% has been reported with all bone-seeking radio-pharmaceuticals, and the response appears to beinversely proportional to disease extent andKarnofsky index [133, 135].
Several detailed dosimetric studies have beenreported for bone-seeking radioisotopes. All theradiopharmaceuticals have shown an approximatetenfold therapeutic ratio between the metastasisand bone, although there is an order of magnitudedifference in absorbed dose calculations (5–50 Gy)between individual metastases [133, 135, 140].Radiation dosimetries for 89Sr-chloride, 153Sm-lexidronam (153Sm-EDTMP), and 186Re-etidronate(186Re-HEDP) are reported in Table 6 [141].
Hematological toxicity is the dose-limitingfactor, usually presenting as thrombocytopenia.Although there is a clear relationship betweenmetastatic burden and toxicity, the correlationbetween thrombocytopenia and absorbed dose
Table 6 Radiation dosimetry of radiopharmaceuticalsused for treatment of refractory metastatic bone pain
Organ
89Sr-chloride(mGy/MBq)
153Sm-EDTMP(mGy/MBq)
186Re-HEDP(mGy/MBq)
Bonesurface
17.0 6.8 1.4
Bonemarrow
11.0 1.5 1.3
Lowerbowelwall
4.7 0.01 0.57
Bladderwall
1.3 1.0 0.54
Testes 0.8 0.005 0.008
Ovaries 0.8 0.009 0.019
Kidneys 0.8 0.02 1.5
From Bodei et al. [141], with permission
26 M. Salvatori et al.
calculations is difficult to be noticed [133] eventhough there have been some exceptions [142].
The bone-seeking agent of choice has not yetbeen determined. Since all the commonly usedradiopharmaceuticals have similar efficacy pro-files, the agent should be selected in a case-basedfashion taking into consideration the availability,toxicity, and goal of therapy.
It is intriguing that all studies that havesearched for a dose–response relationship havefailed to show a correlation between absorbeddose to metastasis and clinical response. Someof these calculations have shown clinical re-sponses at absorbed doses for which classicalradiobiological paradigms would predict no like-lihood of response. Furthermore, no correlationshave been found with primary endpoints, such asoverall survival.
Recently, many clinical trials have shown thesafety and efficacy of the 223Ra-dichloride forpatients affected by metastatic castration-resistant(hormone-refractory) prostate cancer (CRPC),leading to approve the 223Ra-based drug(Xofigo#) for the treatment of adults withCRPC, symptomatic bone metastases, and noknown visceral metastases. For the first time, ther-apy with a bone-seeking agent showed a lifeexpectancy longer than that of patients in theplacebo group, delaying the start of bone fracturesand pain [143]. 223Ra is a calcium mimetic (half-life 11.4 days) alpha emitter. The high linearenergy transfer (LET) of alpha radiation givesrise to a greater biological effectiveness thanbeta radiation and to cytotoxicity that is indepen-dent of dose rate, cell cycle growth phase, andoxygen concentration [144]. The range of alphaparticles (<100 μm) is much shorter than that ofbeta radiation, causing less hematological toxicityfor a given absorbed dose to the bone surface thanbeta emitters [145]. Actually, several trials areongoing for dose escalation and combination ther-apy (e.g., with hormone therapy). 223Ra emits alsoa small number of photons useful for imaging, soin vivo image-based dosimetry is feasible (eventhough challenging), allowing investigations on amacrodosimetric scale [146–148], as well as thetraditional microdosimetric approach to study themechanisms of action of the alpha radiation [144].
Biological Dosimetry
Study of the biological effect induced by ionizingradiation on living organisms has systematicallyrelied on the analysis of cytogenetic indicators,requiring the definition of several theoreticalapproaches to be interpreted [149]. Biologicaldosimetry, based on the investigation of biophys-ical and biological endpoints to estimate absorbeddose, is usually employed in cases of actual orsuspected radiation overexposure. Although sev-eral biological samples can be considered repre-sentative of individual exposure, dose assessmentis usually performed on peripheral lymphocytes.This cell population represents a suitable biologicalmodel to investigate radiation-induced effects,since it circulates in the body and remains quies-cent in the G0 stage of the cell cycle for a relativelylong time.
Chromosomal aberrations induced by ionizingradiation can be classified as stable or unstableabnormalities. Stable anomalies, being consistentwith cell survival, can persist for many years andinvolve reciprocal, nonreciprocal, and interstitialtranslocations. Unstable anomalies, inducing mito-tic cell death, decrease with time and include di-centrics, centric rings, and acentric aberrations.Chromosomal aberrations scored in lymphocytesrepresent a suitable long-term biomarker of whole-body exposure and provide a fairly accurate indexof bone marrow dose [149]. The estimate of in-dividual exposure is obtained comparing thedose–effect relationships of aberrations measuredby scoring with the dose–response relationshipsobserved in in vitro models.
Biological dosimetry may be particularly use-ful in the assessment of individual response toradiation, providing an important contribution tothe development of personalized therapy planningand radiation protection, as well as to establishradiation-induced risk and drugs effects, meant todecrease the radiation-induced side effects.
Although the efficacy of biological dosimetryis established in many cases, the method has somelimitations. Accurate dose assessment in caseof RNT can be very complex, because of theinhomogeneities in body irradiation and theLDR of irradiation. Correction for inhomogeneous
Radiobiology and Radiation Dosimetry in Nuclear Medicine 27
irradiations can be performed, employing contam-inated Poisson distribution method. The distri-bution of observed aberrations among cells iscompared with that expected from a normalPoisson distribution. Nevertheless, a large numberof aberrations, not always achievable, are required[150]. In case of LDR of exposure, the compari-son with in vitro exposure can be hazardous.Indeed, repair can occur during exposure, re-ducing the quadratic component with dose ratedecreasing as exposure is spread over a longerperiod of time [150]. No valid solution for thisproblem has yet been developed.
Furthermore, biological dosimetry assessmentis complex when long retrospective dosimetry isneeded, because of disappearance of lymphocytescarrying unstable aberrations [150]. Several yearsafter exposure, scoring of stable aberrations mightappear more appropriate, although involving morelaborious and expensive techniques (G-banding,FISH). The sensitivity of biological dosimetry isreduced when doses are very low (e.g., below0.1–0.2 Gy), because of the relevant contributionfrom environmental factors (light, chemicals, oxi-dative species originated by metabolism, smoking,and aging) to DNA damage. Moreover, individualvariability in repair of radiation damage can affectdosimetry outcome. Finally, the biological effectson circulating lymphocytes due to exposure of lowradiation doses are sparse and difficult to measure,so cumulative radiation exposure can be slightlyunderestimated.
Assays in Biological Dosimetry
DicentricsOne of the most commonly used biology dosim-etry assay is the count of dicentric chromosomes,selected as suitable biomarkers because of theirrare spontaneous occurrence and their specificityfor ionizing radiation [149].
Despite the high specificity observed for acuteexposure radiation damage, the method appearscumbersome and unsuitable for dose assessmentwith prolonged delayed blood sampling. Even iflymphocytes with aberrations continue to circulatein peripheral blood for many years after irradiation,
a delay longer than 6 weeks between irradiationand sampling can cause reduction in aberrationyield, with a consequent dose underestimation.
Chronic exposures may not be easily deter-mined by dicentric aberration scoring. It wouldbe reasonable to postulate that repair must play asignificant role in the effects of LDR. A study byM’Kacher et al. [151] described the use of biolog-ical dosimetry in patients receiving repeated treat-ments with 131I-iodide for differentiated thyroidcancer (DTC), resulting in cumulative doses from1.0 to 3.5 Gy. A reliable retrospective dosimetrybased on chromosomal aberration analysis (num-ber of dicentric and chromosome 4 painting) wasachieved only for samples collected following thefirst two treatment cycles but not from the thirdtreatment and onward. At this stage, estimateddoses were considerably lower than those deliv-ered, suggesting that apoptosis occurring in lym-phocytes with multiple chromosomal anomaliescould affect the dosimetry outcome followingrepeated irradiations [151].
MicronucleiMicronuclei (MN) can be the result of small acen-tric chromosome fragments that are not incorpo-rated into the daughter nuclei during cell division.They are enveloped by a nuclear membrane andappear as small nuclei – micronuclei – in the cyto-plasm outside the main daughter nuclei. They ariseduring exposure to various clastogenic agents andare the result of non- or misrepaired DNA double-strand breaks. Because of its high reliability andreproducibility, the MN assay has become one ofthe standard cytogenetic techniques for genetictoxicology testing in human and for mammaliancells in general [149].
The baseline, spontaneous frequency of MN isquite variable and can be affected by factors relatedto diet, age, and gender. Such variability clearlyposes limitations on using MN as a biologicaldosimeter, particularly for low doses where pre-existing individual background frequencies arenot known.
The MN assay in peripheral blood lymphocytesis an appropriate biological dosimetry tool to eval-uate in vivo radiation exposure and to assess in vitroradiosensitivity and radiation risk. Many studies
28 M. Salvatori et al.
showed that the number of radiation-inducedMN isstrongly correlated with radiation dose and radia-tion quality, but sensitivity of the assay is limited to0.2 Gy. This is due to the relatively high and vari-able spontaneous MN yield that is an inherent lim-itation of the assay for low-dose estimation. Thespontaneous MN yield increases systematicallywith age, and MN disappearance is very similarto that observed for dicentrics. This result is inagreement with the decline in the MN frequencyfollowing irradiation (around 60%, 1-year post-treatment), observed in patients undergoingradiotherapy.
In a study by Monsieurs et al. [152], the MNassay was used to estimate the radiation-associatedrisk in patients receiving 131I-iodide treatment forhyperthyroidism and thyroid remnant ablation aftersurgery for thyroid carcinoma. Surprisingly, thenumber of micronuclei induced by the differentprocedures, although the activity of 131I-iodidewas much higher in the thyroid cancer group, wassimilar. When this was compared to MN inductionby EBRT in patients with cervical carcinoma orwith Hodgkin’s lymphoma, it was seen that EBRTwas associated with a much higher degree of radi-ation toxicity. The author concluded that this mighthave been a suitable explanation of the differentrates of induction of secondary cancer observed inthe two therapeutic approaches.
A recent study employed the MN assay toevaluate the radioprotective effect of ginkgobiloba extract (GBE). It was demonstrated thatthe use of GME significantly reduced the numberof MN after 131I ablation therapy in thyroid cancerpatients [153].
Chromosome Painting
Fluorescence in situ hybridization (FISH) allows arapid and accurate characterization of chromosomeor chromatid region by using specific DNAsequences labeled with fluorescent molecular pro-bes. FISH painting is a single rapid method, allo-wing simultaneous evaluation of many types ofaberration (dicentrics and single or complex trans-locations) [149]. Accuracy in translocation detec-tion can be improved by using multiple color
painting. Although dicentrics are less stable thantranslocations, they have background frequenciesthat are lower in unexposed people. This makes iteasier to detect the effects of lower exposure doses,provided that exposure was recent and acute. Incontrast, the relative stability of translocationsmakes them more suitable for analysis of chronicor temporally displaced exposures. Although trans-location frequencies were initially thought by someinvestigators to be fully persistent, many studieshave observed their decline with time followingexposure, in some cases reaching a dose-relatedplateau [153].
Comet Assay
The comet assay (single-cell gel electrophoresis)is a fast, sensitive, and not expensive technique tomeasure DNA damage in a single cell [154]. Atvariance with the cytogenic assays previouslydescribed, the comet assay can be performed inany phase of the cell cycle, cells do not need to becultured, and sterile conditions are not required. Itcan be applied to all cell types, only a few hun-dreds are needed, and by this technique it is pos-sible to measure single- or double-strand DNAbreaks and the apoptotic index.
In the comet assay, cells are mixed with aga-rose and layered on microscope slides, where theyare lysed and subjected to electrophoresis; stain-ing with fluorescent dyes such as DAPI orethidium bromide permits microscopic visualiza-tion of the “comets.” DNA containing breaksunwinds and migrates away from the “head” (thenucleus), forming a “tail”; quantification of theamount of DNA in tails and in heads of cometsprovides an estimate of the frequency of strandbreaks. Chromosomal aberrations measured bycomet assay do not last long, since they can eitherbe repaired or lead to cell death [155].
Gutierrez et al. [156] used the comet assay tomeasure the radiation damage in patients treatedwith 131I-iodide for hyperthyroidism, reportingonly a slight increase in DNA breaks 1 monthafter treatment. These results, however, were lessclear to interpret compared to the MN assay,owing to the high sensitivity of the test, but the
Radiobiology and Radiation Dosimetry in Nuclear Medicine 29
poor specificity that may affect the results espe-cially in longitudinal studies.
g-H2AX
The nucleosomal core histone variant γ-H2AXforms part of the cellular DNA damage response.Exposure to ionizing radiation triggers the large-scale activation of specific DNA damage signalingand repair mechanisms. This includes the phosphor-ylation of H2AX in the vicinity of a DSB. Foci ofphospho-H2AX (γ-H2AX) form over large chro-matin domains surrounding DSBs. The formationand loss of γ-H2AX foci have been measured fol-lowing exposure to radiation doses as low as1 mGy, and foci yields have been shown to increaselinearly with dose [157]. Moreover, the initial num-ber of γ-H2AX foci formed per cell nucleus follow-ing ionizing irradiation agrees with the yield ofinduced DSBs. Foci disappearance over time fol-lows DSB rejoining in repair-competent cells; thereis a close one-to-one relationship between initialand residual radiation-induced DSBs and γ-H2AXfoci. These include rapid and potentially automat-able processing and analysis, sensitivity to dosesof a few milligrays, linear dose response acrossa broad dose range, ability to use unstimulatedlymphocytes obtained by minimally invasive pro-cedures, and potential to reveal partial body expo-sures. A recent article described the use of γ-H2AXin thyroid cancer patients undergoing thyroid rem-nant ablation therapy. The technique was used toassess double-strand breaks starting 0.5–120 h aftertreatment, and it was possible to demonstrate theearly start of DNA damage by a linear dose-dependent increase and a bi-exponential responsefunction describing a fast and a slow repair compo-nent [158].
However, severe limitations associated mainlywith the rapid loss of the γ-H2AX signal followingirradiation have to be considered. They are likely torestrict the use of the γ-H2AX to very recent radi-ation exposures – less than 2 days before bloodsampling. Since the yield of γ-H2AX per unit dosechanges rapidly over time, dose–effect curves for
calibration of the assay are required for multipletime points.
Conclusions
Although dosimetry has been of great value in thepreclinical phase of radiopharmaceutical develop-ment, its clinical use to optimize administered activ-ity on an individual patient basis has been lessevident. Similarly, little attention has been paidto radiobiology in therapeutic nuclear medicine,which exhibits significant differences with respectto the biologic effects of EBRT. However, data inthe literature which underscore the potential ofdosimetry to avoid under- and overdosing and theimportance of radiobiology in RNT are increasing.
The recent proliferation of PET/CT andSPECT/CT cameras, the development of patient-specific 3D imaging-based dosimetry, and theavailability of faster computers and improvedMonte Carlo methods will offer more and moremajor scientific and clinical opportunities in RNTdosimetry improving the physics of absorbed doseestimation. Furthermore, the increasing scientificinterest in the radiobiological features specific toradionuclides will improve our knowledge innuclear medicine therapy and will advance ourability to administer this treatment modalityoptimally.
As stated by Edith Quimby in 1969 “Radionu-clide dosimetry is not a finished product, but it hascome a long way from the early empiric days. Wemust be grateful to the patient people who havespent untold hours on these developments” [158].
Diagnosis
By incorporating adequately large activities ofappropriate radionuclides into target tissue-avidradiopharmaceuticals, a sufficiently high radiationdose can be delivered to produce a therapeuticresponse in tumors or other tissues. However,such high administered activities can alsoensue some radiation injury in normal tissues.
30 M. Salvatori et al.
Nevertheless, nuclear medicine remains largely adiagnostic specialty, where relatively low admin-istered activities are administered to yield impor-tant clinical information whose benefit faroutweighs the small potential risk associatedwith the attendant low normal tissue radiationdoses. The radiation doses associated with diag-nostic administration of radiopharmaceuticals aretypically of the order of 1 cSv [159], well belowthe threshold doses associated with the determin-istic effects of radiation described in the priorsection. Average normal tissue doses are receivedby the “standard” patient, found in package insertsfor approved radiopharmaceuticals and in reportsissued by authoritative bodies such as the Interna-tional Commission on Radiological Units (ICRU),even though the actual doses received by a partic-ular patient may deviate significantly from theseaverage values. For such procedures, the radiationeffects of practical concern are stochastic (or statis-tical) effects, i.e., possible germ-cell mutagenesisand, in particular, carcinogenesis.
Medical Radiation Exposures: SocietalConcerns
The clinical applications of diagnostic nuclearmedicine, particularly PET and nuclear cardiology,as well as computed tomography (CT), have growndramatically over the last several decades. In theUSA, for example, the annual number of nuclearmedicine procedures has increased threefold (from7 to 20 million) and the annual number of CTprocedures 20-fold (from 3 to 60 million) between1985 and 2005 [160], much of the increase in thelatter being related to the use of CT in children (upto � 10% of all such procedures). As a result ofthis increased medical exposure of the population,the average (i.e., per capita) annual backgrounddose in the USA has nearly doubled, from 3.0 to5.6 mSv [161]. There has been increasing concernin the medical profession and in the popular pressover the potential public health impact – namely, anincreased risk of cancer – associated with thisdramatic growth in exposure from diagnostic
radiology and nuclear medicine. Brenner andHall, for example, have estimated that as much as2% of all cancers in the USAmay be attributable toCT irradiation [162]. While nuclear medicine diag-nostic procedures are not performed as frequentlyas CT scans and the radiation doses are generallynot as high, the radiogenic cancer risk per proce-dure is comparable. For all the diagnostic proce-dures, the relevant parameters should always bejudiciously selected to deliver the minimum radia-tion dose consistent with yielding the clinical infor-mation being sought, according to a commonsenseapproach as emphasized in the “Image Gently”campaign [163–166] promoted by many agenciesand professional organizations.
Nuclear medicine practitioners must be pre-pared to rationally address the “cancer-risk” con-cerns of patients, referring physicians, regulators,and other stakeholders.
Radiation Doses in Diagnostic NuclearMedicine
RadiopharmaceuticalsTable 7 is a compilation of radiation doses forcommon diagnostic nuclear medicine proceduresin terms of the effective dose (ED) for the 70-kgstandard adult anatomic model [159, 167, 168].Effective dose is used in radiation protection tocompare the stochastic risk of a nonuniform expo-sure to ionizing radiation with the risk associatedwith a uniform whole-body exposure. It is aweighted sum of the doses to the individual tis-sues/organs of the body, where the tissue weightingfactor reflects the relative susceptibility of that tis-sue to stochastic damage (i.e., carcinogenesis or, inthe case of germ cells, germ-cell mutagenesis). EDsfor such procedures are usually of the order of 1 cSvfor typical administered activities, meaning that theoverall risk of carcinogenesis (and germ-cell muta-genesis) is roughly equivalent to that of a uniformwhole-body dose of 1 cGy. Anatomic modelsand relevant dosimetric quantities such asabsorbed fractions are now available [168], andradiopharmaceutical doses have thus been
Radiobiology and Radiation Dosimetry in Nuclear Medicine 31
estimated for newborns, 1-year-olds, 5-year-olds,10-year-olds, and 15-year-olds as well as adults[168–170]. There is typically a several-fold orgreater difference in doses among organs for a
particular radiopharmaceutical and anatomicmodel [171] for fluorine-18-labeled fluoro-deoxyglucose ([18F]FDG) in the Standard Adultanatomic model. Furthermore, as emphasized by
Table 7 Radiation doses for diagnostic nuclear medicine procedures for the 70-kg standard man anatomic model
several authors [172–174], one should use organ-,age-, and gender-specific doses and risk factors,rather than the ED and the overall risk factor, toestimate the cancer risk(s) associated with a partic-ular procedure.
Multimodality Studies: PET/CTand SPECT/CT
As noted, there has been growing concern regard-ing the radiation dose associated with CT studies,particularly for the pediatric patient population[162, 172]. When CT is performed as part of aSPECT/CT or a PET/CT study, the axial field ofview may be much larger than that of conven-tional CT studies, routinely extending from thebase of the skull to the mid-thigh and thus poten-tially yielding an ED considerably greater thanthat of conventional, limited field-of-view CTstudies [175]. Accordingly, when the CT compo-nent of a PET/CT study is used for attenuationcorrection and anatomic localization rather thanfor radiologic diagnosis, the CT scan parameterscan, and should, be adjusted to appropriatelyreduce the CT dose. X-ray beams are character-ized by (1) the current (expressed in units ofmilliampere (mA)) between the anode and cath-ode and (2) the maximum or peak (p) voltage(expressed in thousands of volts (V), or kilovolts(kV), and represented as “kVp”) between the fil-ament and the metallic target, where the electronsaccelerated across this potential difference arestopped and the bremsstrahlung X-rays produced.Helical, or spiral, CT scans are also characterizedby the pitch, the distance of travel of the patienttable per rotation of the X-ray tube, and detectorassemblies. The X-ray intensity and therefore theradiation dose are proportional to the mA andapproximately proportional to the square of thekVp value. The dose is inversely related to thepitch. To determine the minimum-dose CT acqui-sition parameters that are compatible with accu-rate attenuation correction, investigators havesystematically evaluated the impact of suchparameters and therefore patient dose on bothCT and PET image quality. Kamel et al. [176],for example, found no significant effect of tube
current (10, 40, 80, and 120 mA) on [18F]FDGstandard uptake values (SUVs) and measuredlesion sizes, with no significant difference inSUVs and lesion sizes between 68Ge- and CT(80 mA)-attenuation-corrected PET scans. Theauthors concluded that CT scans using tube cur-rents as low as 10 mA yield adequate attenuationcorrection for PET. Fahey et al. [175] subsequentlyevaluated the dose from the CT component ofPET/CT studies to determine minimum-dose CTacquisition parameters (10, 20, 40, 80, 160 mA;80, 100, 120, 140 kVp; 0.5 and 0.8 s per rotation;1.5 pitch) that provide adequate attenuation cor-rection for a range of patient sizes (i.e., anatomicphantoms) from newborns to adults. The CT doseindex (CTDI), a commonly used CT dosimetryparameter indicative of the ED, varied by twoorders of magnitude for each phantom over therange of acquisition parameters (e.g., for the10-year-old-sized phantom, the CTDIs were0.030 and 2.1 cSv for 80 kVp, 10 mAs, and 0.8 sand for 140 kVp, 160 mAs, and 0.8 s, respec-tively). The CTDI for the newborn phantom wastwice that for the adult phantom for the same CTacquisition parameters. The 68Ge rod source dosewas only 0.003 cSv (3-min scan). Although CTstatistical uncertainty (i.e., mottle or “noise”) var-ied substantially among acquisition parameters,its contribution to PET noise was minimal(<�2%). In a pediatric phantom, PET imagesgenerated using CT performed with 80 kVp and10 mA for attenuation correction were qualita-tively and quantitatively indistinguishable fromthose generated using CT performed with140 kVp and 160 mA. Importantly, however,with very low-dose CT (80 kVp, 10 mA) forthe adult phantom (i.e., for the combination ofboth low kVp and low mA), systematicundercorrection of the PET data for attenuationresulted. The impact on dose of these differentCT acquisition parameters is significant.A diagnostic-quality CT (e.g., with “standard”kVp of 140, mAs of 190, and pitch of 1.25)delivers an ED of 2.2 cSv [175, 177–179] andtherefore a total ED of 3.3 rem. However, forattenuation correction of an [18]FDG PET scanin an adult, a quantitatively accurate but non-diagnostic CT scan (e.g., with a kVp of
Radiobiology and Radiation Dosimetry in Nuclear Medicine 33
120, mAs of 60, and pitch of 1.5) delivers an EDof only 0.60 cSv [175, 177–179] and therefore atotal ED of 1.7 cSv. For smaller patients a tubecurrent as low as 60 mA can be used (with a kVpof 120 and a pitch of 1.5); the CT ED is only0.1 cSv [175, 177–179]. Thus, if the purpose ofthe CT component of a SPECT/CT or PET/CTstudy is attenuation correction and anatomic reg-istration and not radiologic diagnosis, appropri-ately judicious selection of the CT parameters canreduce the total ED by over 50% without com-promising the diagnostic information content andquantitative accuracy of the PET study.
The largest and best characterized human cohortexposed to significant amounts of ionizing radia-tion remains the A-bomb survivors in Hiroshimaand Nagasaki. Not surprisingly, A-bomb dosime-try had long been uncertain and plagued by anumber of unresolved issues, including the yieldof the Hiroshima bomb, the dose contribution ofactivation products, and the RBE and magnitude
of the neutron dose. The latest A-bomb dosimetrysystem, Dosimetry System 2002 (DS02), im-proves on the Dosimetry System 1986 (DS86)and earlier A-bomb dosimetry systems in manyimportant details, including the specifics of theradiation released by the bombs, addition of sig-nificant numbers of survivors to the so-called LifeSpan Study (LSS), and the effects of shielding bystructures and terrain, and has thus resolved manyof the outstanding dosimetric issues [180].
Choice of the correct model (i.e., mathematicalrelationship) between the excess cancer risk andradiation dose for extrapolation of the A-bombdose–response data from its historical “high-dose” (>100 cSv) range to the diagnostic or“low-dose” (<10 cSv) range has long been con-troversial. The basic choices for such a mathemat-ical extrapolation model are the supralinear model,the sublinear (i.e., linear-quadratic) model, and thelinear, no-threshold model (Fig. 4). A supralinearmodel implies that the cancer risk per cSv is actu-ally higher at low doses than at high doses; thereare no data or biophysical evidence to supportsuch a model that has never been creditably con-sidered. The sublinear (i.e., linear-quadratic)model has for many years been the generally
0
Currentlower limitof A-bomb
survivor data:~5 cSv
Currentprevailing model
BEIR V/VIILinear
No-threshold Model
Previousprevailing model
Pre-BEIR V
Supra-LinearModel
Supra-Linear(Linear-Quadratic)
Model
Data
Historicallower limitof A-bomb
survivor data:~100 cSv
Radiation Dose
Exc
ess
Can
cer
Inci
denc
e
Fig. 4 Schematicrepresentation of the basicchoices for mathematicalextrapolation of theA-bomb dose–response(i.e., excess cancer riskvs. radiation dose) datafrom its historical “high-dose” (>100 cSv) range tothe diagnostic or “low-dose” (<10 cSv) range
34 M. Salvatori et al.
accepted dose–response model. The availablehuman data are generally consistent with such amodel, as are certain biophysical models of radi-ation action at the molecular level. Importantly,the sublinear model implies that the risk per cSvis lower at lower doses than at the higher doses(at which data are actually available). With thepublication of the BEIRVand BEIRVII Reports[181, 182], however, the linear, non-thresholdmodel is now the prevailing model for solidtumors, while the linear-quadratic model is themodel of choice for leukemias [181, 182]. Thelinear, non-threshold model implies that the riskper cSv is constant at all doses, and it furtherimplies that any excess radiation dose (i.e.,above background), no matter how small, carrieswith it a finite (i.e., nonzero) excess risk of cancerand genetic damage. The available A-bomb sur-vivor data for solid tumors – now including sig-nificant numbers of survivors receiving doses aslow as 5 cSv on the basis of DS02 [180, 183] –are consistent with the linear, non-thresholdmodel as well as with the linear-quadraticmodel. That is, on the basis of statistical consid-erations such as goodness-of-fit, one cannot actu-ally distinguish between the sublinear (i.e.,linear-quadratic) and the linear, non-thresholdmodels. The linear, non-threshold model ismore conservative (i.e., predicts a higher riskper cSv at low doses) than the sublinear modeland is therefore considered “safer” and thus moreappropriate by some for radiation protection pur-poses. As noted, however, this issue remainscontroversial.
The BEIR VII age at exposure- and gender-specific risk factors for solid tumor and leukemiaincidence and mortality shows pronounced differ-ences in radiogenic cancer risk (in terms of bothincidence and mortality) depending on age atexposure and gender (especially at youngerages); there are large differences depending onthe cancer site, with female breast, lung, colon,and urinary bladder being the most susceptible toradiation-induced cancer [182]. The risk factorsincorporate a so-called dose-rate effective factorof 1.5, meaning that HDR (> � 10 cSv/min orhigher) radiation has a 50% higher risk factor thanLDR (<�1 cSv/min or lower) [182]. It is
possible, however, that the dose-rate effectivenessfactor may actually be higher than 1.5 and that therisk factors may therefore overestimate somewhatthe cancer risk associated with the LDRs typicalof diagnostic radiopharmaceuticals. Moreover,although stratified by age and gender, the riskfactors within each stratum represent population-averaged values and thus do not account for indi-vidual differences in radiation sensitivity relatedto any preexisting condition, genetic susceptibil-ity to radiogenic damage, etc. [174]. Importantly,as noted by Brenner and colleagues [162, 184],the risk factors they employed to estimate thenumbers of radiogenic cancers associated withCT scanning are based on A-bomb incidencedata at doses as low as 5 cSv – comparable tocumulative doses actually received by patientsundergoing multiple CT procedures (as is oftenthe case clinically) [4] – and not model-basedextrapolation from higher (i.e., “supra-clinical”)-dose data.
Risk–Benefit Considerations
Our discussion thus far has focused on the risks,most notably, the risk of cancer, associated withlow (i.e., diagnostic)-level radiation – to theexclusion of any concrete consideration of itsmedical benefit. This is rather typical in the sci-entific literature: other than a perfunctoryacknowledgment that the benefits of diagnosticprocedures far outweigh any radiogenic risks,such benefits are rarely, if ever, quantitated in amanner comparable to that of quantitation of risk.An unintended consequence of such “unbal-anced” analyses – that is, quantitation of riskwithout comparable consideration of benefit –may be the mistaken perception that the medicalbenefit of a diagnostic procedure does not faroutweigh radiogenic risk. Alternatively, the lackof quantitation of benefit may result in proceduresin which risk outweighs benefit unjustifiablypersisting in clinical practice. As illustrated bythe case study which follows, risk–benefit ana-lyses should thus quantitatively incorporate boththe medical benefit and the radiogenic risk ofdiagnostic procedures.
Radiobiology and Radiation Dosimetry in Nuclear Medicine 35
Van Tinteren et al. [185] compared the manage-ment and clinical of suspected non-small cell lungcancer (NSCLC) with and without preoperative[18F]FDGPET.With the conventional preoperativeevaluation of NSCLC, that is, without [18F]FDGPET, 81% of patients underwent thoracotomy, and41% of those thoracotomies were futile, that is,non-potentially curative, because of the progres-sion of disease disclosed at surgery. In series ofVan Tinteren et al. [185], the surgery-related mor-tality was 6.5%. Adding [18F]FDG PET to thepreoperative evaluation reduced the proportion ofNSCLC patients undergoing thoracotomy to 65%,with only 21% being futile. Thus, a non-curativeoperation was avoided in 20% of patients with theaddition of [18F]FDG PET. If one extrapolates theforegoing data to the US population, with 174,470new lungs per year, the conventional preoperativeevaluation will result in 174, 470� 0:81� 0:41�0:065 ¼ 3, 766 futile surgical deaths each year; theaddition of [18F]FDGPET to the preoperative eval-uation reduces the number of futile surgical deathsper year to 174, 470� 0:65� 0:21� 0:065 ¼ 1,
547 – a gross benefit of [18F]FDG PET3,766 � 1,547 = 2,219 lives saved per year.However, for a 370-MBq administered activityof [18F]FDG, the ED is 1.4 cSv [159] and thenumber of radiogenic cancer-related deaths there-fore 174, 470� 1:4 cSv� 0:0005=cSv ¼ 122,
where 0.0005/cSv is the mean cancer risk factor(i.e., the lifetime age- and gender-averaged fractionalincrease in excess cancer mortality) [182]. Thus, theaddition of [18F]FDG PET to the preoperative eval-uation of suspected lung cancer results in a netbenefit of 2,219 � 122 = 2,097 lives saved peryear. Such a balanced quantitative analysis thusprovides some perspective for objective consider-ation of radiogenic risks and medical benefits.
Considerations for SensitivePopulations: Prospective Parents,Pregnant Women, and NursingMothers
Prospective ParentsExperimental studies in a number of nonhumansystems have established that gonadal irradiation
at sufficiently high doses can result in demonstrableabnormalities in subsequently (i.e., postirradiation)conceived offspring of the irradiated parent(s).Importantly, however, despite comprehensive stud-ies of well over 10,000 children born to the atomicbomb survivors in Hiroshima and Nagasaki receiv-ing mean gonadal doses of over 30 cGy and indi-vidual gonadal doses of up to several hundred cGy,there remains no evidence for heritable radiationeffects in man [182, 186]. Specifically, in childrenborn toA-bomb survivors at least several years afterthe bombings, there was no statistically significantincrease in any radiogenic heritable effect. Thisimplies that for diagnostic nuclear medicine pro-cedures, where the gonadal doses are of the order ofonly 1 cSv (an order of magnitude less the 30-cSvmean gonadal dose received by the A-bomb survi-vors), there is no significant risk of heritable adverseeffects among the offspring of patients whoundergo such procedures. The estimation ofhuman genetic risks is thus based largely on dataderived from laboratory studies in animals, intro-ducing the considerable uncertainty of extrapola-tion from nonhuman systems to humans [187].The estimated absolute and relative risk factors areapproximately 50 additional genetic effects/millionlive births/cSv and approximately 0.01%/cSv,respectively, in the F1 generation [182].
Not surprisingly perhaps, the absence of germ-cell damage in diagnostic nuclear medicine doesnot extend to therapeutic applications of radionu-clides. Although a number of patients are small,demonstrable gonadal damage, such as reducedsperm counts and impaired fertility, may occuramong 131I-iodide therapy patients over the firstyear posttreatment [182]. However, even amongthyroid cancer patients treated with large (GBq)amounts of 131I-iodide and receiving gonadaldoses of the order of 100 cSv, such damage istransient [188, 189]. For example, follow-up stud-ies of such patients indicate that among malepatients there is a time-dependent recovery ofsperm count and serum follicle-stimulatinghormone (FSH) to control levels by 2 years post-treatment [190]. Long-term studies (i.e., 10 yearsor longer posttreatment) among both maleand female patients indicate that fertility andthe frequencies of miscarriages and congenital
36 M. Salvatori et al.
abnormalities among their offspring are compara-ble to control values [190].
Pregnant WomenIt is an established radiobiological principle thatthe conceptus is particularly sensitive to radia-tion effects. Radiation doses to the conceptusassociated with diagnostic procedures – gener-ally of the order of or less than 0.1 cSv per37 mBq administered to the mother [191–198]– are nonetheless well below the threshold dosesfor deterministic effects such as radiogenic fetaldeath or congenital malformations. Althoughmodification of the standard anthropomorphicadult anatomic model [168] has yielded reason-ably accurate dosimetric models of theconceptus–pregnant woman [191, 197, 198],radiopharmaceutical kinetic data in utero andtherefore fetal dose estimates remain quite lim-ited. For such procedures and at such in uterodoses, the practical concern is the increased riskof childhood cancer. Published data, includingthe seminal Oxford Survey of Childhood Can-cers [182, 199], indicate an excess risk of child-hood cancer as high as 20% per Sv received inutero, with a linear response down to doses aslow as 1 cSv. Signs alerting female patients andcontaining wording similar to, “If you are preg-nant or if it is possible you may be pregnant,please notify the staff before the beginning ofany procedure,” should therefore be prominentlyposted throughout a nuclear medicine depart-ment, particularly in waiting and/or dressingareas. Once informed that a female patient ofchildbearing age is pregnant or may be pregnant,the nuclear medicine physician should conferwith the referring physician to arrive at a medi-cally informed, documented decision that theplanned procedure is or is not justified. In partic-ular, because RNT typically involves the admin-istration of high (typically GBq) activities, suchtherapy is generally contraindicated in pregnantwomen, unless there is no viable alternative. Aserum pregnancy test should be performedbefore RNT in any female patient of childbearingage. Assertions by the patient and/or her familyregarding the impossibility of a pregnancy becauseof medical condition, sexual inactivity, use of birth
control measures, or recent menstrual historyshould not preclude performing a serum pregnancytest prior to RNT.
The use of 131I-iodide therapy for thyroid dis-eases in pregnant or potentially pregnant womenis particularly problematic because radiogenicdestruction of the iodine-avid fetal thyroid mayresult from such treatment and may result in hypo-thyroidism in utero with consequent cretinism[200]. The fetal thyroid begins concentratingiodine at the 12th–15th week of gestation, andfetal absorbed doses can be over 1,000 cSv per3.7 GBq administered to the mother, depending ongestational age and maternal thyroid uptake. Thera-peutic administered activities of 0.37–3.7 GBq ofiodine would therefore result in fetal thyroidabsorbed doses from 10,000 to 100,000 cSv,respectively. Case reports that include adminis-tered activity, gestational age, and follow-up ofpregnant women treated with radioiodide forhyperthyroidism or thyroid cancer indicate thatthe outcome of pregnancy with regard to fetalthyroid function at birth did not appear to becompromised in the cases when radioiodide wasgiven before the tenth week of pregnancy. How-ever, there was essentially a 100% risk for con-genital hypothyroidism and/or cretinism whenradioiodine was administered thereafter, even inamounts less than 5 GBq [200]. Pregnancy is thusa contraindication to radioiodide therapy, and asstated above, a serum pregnancy test should beperformed before administration of such therapyin any female patient of childbearing age.
Nursing Mothers
Virtually any systemically administered material,including a radiopharmaceutical, will appear tosome extent in the breast milk of a lactatingfemale, producing high activity concentrations inbreast milk and potentially delivering significantradiation doses to nursing infants [201–206]. Inone study, for example, the cumulative breast milkactivity ranged from 0.03% to 27% of 131I-iodideadministered for thyroid uptake studies [206].Because of an infant’s small size and the inverserelationship between absorbed dose and mass,
Radiobiology and Radiation Dosimetry in Nuclear Medicine 37
ingestion of even a relatively small amount ofactivity will result in proportionately large total-body and organ absorbed doses. Furthermore,because of proximity of the infant to the motherwhen nursing, there is a potentially significantexternal absorbed dose to the infant. Signs alertingwomen with language such as, “If you are breast-feeding, please notify the staff before the begin-ning of any procedure,” should therefore be prom-inently posted throughout a nuclear medicinedepartment. Using a variety of dosimetric criteria(e.g., an effective dose equivalent to the nursinginfant of 0.1 cSv), a number of authors haverecommended different interruption periods priorto resuming breast-feeding following administra-tion of radiopharmaceuticals [201–206]. Theduration of the cessation of nursing will dependon the radionuclide and its effective half-lifein vivo, the administered activity, and the extentto which radioactivity is concentrated in breastmilk. While there is no absolute consensus, thefollowing are representative of the published rec-ommendations: 24 h following any administrationof 99mTc, 2–4 weeks following administration of67Ga-gallium citrate, and permanently for thecurrent nursing infant following any administra-tion of 131I-iodide, especially for administration oftherapeutic amounts of 131I.
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