Radiobiology and Radiation Dosimetry in Nuclear Medicine

  • Massimo SalvatoriEmail author
  • Marta Cremonesi
  • Luca Indovina
  • Marco Chianelli
  • Massimiliano Pacilio
  • Carlo Chiesa
  • Pat Zanzonico
Living reference work entry


Radionuclide therapy (RNT) uses systemically administered radiopharmaceuticals directed to a specific cancer-associated target to provide low-dose-rate (LDR) treatment. The radiation dose is delivered to the tumor cells by continuous, but declining, exposure that is a function of the initial uptake and the variable half-life. The average dose rate for RNT is typically of the order of 2–8 Gy/day, and the maximum absorbed dose may be up to 50 Gy delivered over a period of many days. This is in marked contrast to the situation with external beam radiotherapy (EBRT), where the dose is delivered at a high-dose rate (HDR), typically 1–5 Gy/min, and also in contradistinction to the dose rate at which brachytherapy is delivered, typically 1–5 Gy/h. The mechanisms by which cells respond to LDR exposures are fundamentally different from those occurring at HDR. LDR exposures tend to promote loss of clonogenic potential in some cell types (e.g., lymphomas) by activating apoptotic responses, whereas high doses tend to cause necrosis as their primary mechanism of cytotoxicity. The ability to induce apoptosis varies inversely with dose rate. Many cell types exhibit an initial hypersensitive response at doses below ∼25 cGy followed by a region of increasing radioresistance up to ∼50 cGy. This phenomenon probably involves an alteration in the cellular processing of DNA damage as a function of dose. Radiation damage to cells is due primarily to indirect effects such as formation of free radicals in water (with their diffusion and subsequent interaction with cellular components, mostly DNA) and to some degree direct damage to DNA. Different tissues and different individuals have different abilities to respond to and repair this damage. The value of LDR therapy with radionuclides in patients with differentiated thyroid carcinoma, somatostatin receptor-expressing tumors, neuroendocrine tumors, lymphoma, liver tumors, and treatment of metastatic bone pain is discussed.


Radionuclide therapy Radiobiology Radiation dosimetry Therapeutic radiopharmaceuticals DNA damage and radiation dose 







Autologous stem cell transplantation


Biologic effective dose


Body surface area


Castration-resistant prostate cancer


X-ray computed tomography


CT dose index


Dimercaptosuccinic acid


1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid




DOTA- Tyr3-octreotate


Double-strand breaks


Differentiated thyroid cancer


Diethylenetriaminepentaacetic acid


Dose–volume histograms


European Association of Nuclear Medicine


External beam radiation therapy


Ethyl cysteinate dimer


Effective dose


European Union


United States Food and Drug Administration


Fluorescence in situ hybridization


Follicle-stimulating hormone


Ginkgo biloba extract




Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)


Hepatocellular carcinoma


High-dose rate


Hexamethylpropylenamine oxine


International Commission on Radiological Units


Low-dose hyper-radiosensitivity–increased radioresistance




Linear energy transfer


Lethal–potentially lethal




Lung shunt fraction


Life span study


Macroaggregated albumin




Methylene diphosphonate




Medical internal radiation dose


Magnetic resonance imaging




Noradrenaline transporter


Non-Hodgkin’s lymphoma


Non-small cell lung cancer


Non-tumor tissue


Normal tissue complication probability


Organ level internal dose assessment


Positron emission tomography


Positron emission tomography/Computed tomography


Positron emission tomography/Magnetic resonance imaging


Peptide receptor radionuclide therapy


Relative biological effectiveness


Relative effectiveness per unit dose


Radio induced liver disease




Region of interest


Reactive oxygen species


Surviving fraction


Society of Nuclear Medicine


Single-photon emission computed tomography


Single-photon emission computed tomography/Computed tomography


Stress or aberrant signaling-induced senescence


Standardized uptake values


Unit of radiation absorption in the International System of Units (SI), which takes into account the relative biological effectiveness (RBE) of ionizing radiation


Transarterial chemoembolization


Trans-arterial radioembolization


Total-body absorbed


Tumor control probability


Tumor necrosis factor


TNF-related apoptosis-inducing ligand


Volume of interest


Whole-body radiation dose


Whole-body scan


Phosphorylated member X of the H2A histone family

New radiopharmaceuticals have led to increasing success of radionuclide therapy (RNT) [1, 2]. To plan treatment with RNT requires understanding dosimetry to both the target organ and other sites of tracer localization [3, 4]. However, despite the fact that maximizing radiation-absorbed dose to tumor while minimizing damage to normal tissues is the central objective of RNT, up till now RNT dosimetry has not gained wide acceptance as a necessary clinical tool. The need for dosimetry to individually optimize the therapeutic activity to be administered has been far from self-evident, and efforts in this direction are in an infancy stage [4].

This chapter describes the progress that has been achieved in the fields of dosimetry and radiobiology, including a brief overview of the techniques used in biological dosimetry.


There are three major approaches to the delivery of radiation therapy to treat patients with cancer: (1) locoregional delivery, such as in external beam radiotherapy (EBRT), (2) sealed-source interstitial/intracavitary radiotherapy (brachytherapy), and (3) RNT which include the use of receptor-directed ligands, metabolic precursors, or monoclonal antibodies (i.e., radioimmunotherapy) [5].

The key clinical and basic characteristics of RNT are the systemic administration of a radiopharmaceutical directed to a specific cancer-associated target and the rate at which the radiation dose is delivered to that target [5].

According to the principle of very low-dose rate (LDR), in RNT the radiation dose is delivered to the tumor cells by continuous, but declining, exposure that is a function of the initial uptake and the variable half-life. The average dose rate for RNT is typically of the order of 2–8 Gy/day, and the maximum absorbed dose may be up to 50 Gy delivered over a period of many days. This is in marked contrast to the situation with EBRT, where the dose is delivered at a constant high dose rate (HDR), typically 1–5 Gy/min, and also at variance with the dose rate brachytherapy is delivered, 1–5 Gy/h [5].

To date, most radiobiological models of RNT have been based on the extrapolation of data obtained following homogeneous exposures to acute single or fractionated doses of EBRT and have assumed that EBRT and RNT administered are substantially equivalent from the biological point of view. However, emerging evidence suggests that the mechanisms of cellular response to LDR exposures are fundamentally different from those occurring at HDR with either EBRT or brachytherapy [3, 6].

The combination of prolonged response, limited toxicity, and the ability to treat on multiple occasions suggests that the mechanism of action of LDR therapies is different from that seen with HDR exposures. Accordingly, treatment plans, clinical trials, and outcome assessment should be designed to consider this difference. Current radiobiological research points to a way in which RNT can be more effectively administered to patients by taking into account the biology of the mechanism of action of therapy as well as the physical characteristics of the radionuclide [5].

Conventional Radiobiological Models

A number of basic principles, emerged from early studies describing the effects of acute single or fractionated doses of EBRT on the clonogenic survival of cells, generally held that a cell must be “hit” by a radiation track in order to be killed, that genomic DNA was the principal “target” for killing, and that double-strand breaks (DSBs)/clustered lesions/multiply damaged sites were the principal DNA lesions leading to cell death [3].

Early models focused largely on the mechanical or metabolic challenges that DSBs might pose to a cell when it attempts to replicate its DNA (in S-phase) or divide (in mitosis). The linear-quadratic (LQ) model of fitting and interpreting clonogenic cell survival curves became a cornerstone of experimental radiation oncology and indeed is still widely used for predicting the clinical impact of changes in dose fractionation or dose rate on biological effect [5].

This model assumes two components of cell killing, one proportional to the dose D (αD) and the other is a quadratic term (βD2) in which two sublesions are presumed to interact to produce a lethal event. The relationship between cell survival (surviving fraction, SF) and dose is then described by: \( - \ln \left[\mathrm{SF}\right]=\alpha \mathrm{D}+\beta {\mathrm{D}}^2 \). The two-hit/quadratic (β) term represents the fraction of cell killing caused by damage that can be spared either by dose fractionation or by decreasing the dose rate. In contrast, the one-hit/linear α-type lethal events are independent of time and thus of fractionation or dose rate [3, 5].

Application of the LQ model to HDR exposures indicates that cell killing generally decreases as the dose is fractionated, and this sparing would reflect the repair that takes place between fractions of the individual “sublethal” lesions that, in combination, would otherwise have contributed to β-type cell killing. Survival curves for large numbers of small fractions ultimately approximate the initial slope (α) of the HDR curve.

The typical dose rates used for both clinical EBRT and radiobiological studies are of the order of minutes (∼1–5 Gy/min), exposure times not long enough for DNA repair to occur during the irradiation process. As the dose rate is lowered, the time taken to deliver a given dose increases, and it is then possible for DNA repair to take place during irradiation and for radiosensitivity to gradually decline [3, 5].

Survival curves at decreasing LDR become straighter and ultimately extrapolate the initial slope (α) of the HDR curve, with a sparing effect that would be attributed to the repair of sublethal lesions occurring during the protracted exposure (Fig. 1).
Fig. 1

Conventional dose-rate effect for cell killing as the dose rate is lowered from 150 to 1.6 cGy/min. The dashed curves represent the best fit to the data set obtained using the lethal–potentially lethal (LPL) model assuming either full repair (a) or no repair (b), respectively

At very LDRs (≤2 cGy/min), cell proliferation can occur during the irradiation, thus leading to repopulation of the pool of clonogenic cells. Clearly, based on this assumption, RNT should be ineffective, although this expectation is not consistent with many clinical observations. Such phenomenon, in which decreasing the dose rate results in increased cell killing, has been defined “inverse dose-rate effect.” The effect has been attributed both to the lower-dose rate (permitting the cells to progress through the cell cycle into more radiosensitive phases) and to some hypersensitivity of cells to low-dose/LDR exposures, as will be discussed below [3, 5].

Cell Death Mechanisms

Most cellular responses to ionizing radiation-induced DNA damage are genetically regulated and involve specialized DNA damage-recognition factors that trigger a cascade of signaling events that alter the expression and/or activity of specific genes/proteins involved in cell cycle arrest, DNA repair, accelerated senescence, and apoptosis at the cellular level and in tissue repair at the tissue level [5].

Necrosis, a form of cell death that has been variously described as generalized, nonspecific, accidental, or passive (i.e., it is not a genetically regulated process), generally occurs after high doses in cells that enter mitosis carrying high levels of unrepaired DNA damage [5].

In contrast, apoptosis is an energy-dependent, genetically controlled “suicide” process that involves the activation of degradative proteolytic enzymes called caspases and tends to occur at low doses of radiation. Apoptotic postirradiation cell death is mediated by two pathways, both resulting in activation of the cascade of caspases that function as cell executioners. Firstly, signals from the nucleus or cell membrane can activate the “intrinsic” pathway of apoptosis with a series of sequential events that cause final activation of caspases 3,6,7, and 8. Secondly, the “extrinsic” pathway of apoptosis is mediated by death receptors that are activated by ligands, such as the Fas ligand, tumor necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand (TRAIL). TRAIL induces apoptosis in response to ionizing radiation through the clustering of DR4 and DR5 receptors in the cell membrane [7].

Other modes of cell death are the “accelerated” or “premature” senescence or “STASIS” (stress or aberrant signaling-induced senescence), a genetically programmed response to DNA damage [8], and the mitotic catastrophe, generally defined as the failure of a cell to properly undergo mitosis after DNA damage. It has recently been recognized that mitotic catastrophe is not a mode of cell death per se, but a death that generally occurs secondarily to mitotic catastrophe, apoptosis, or accelerated senescence [9]. Death secondary to mitotic catastrophe has been suggested to account for a significant proportion of the cytotoxicity observed after radiation exposure.

Possible Contributing Mechanisms to RNT Tumor Responses

Low-Dose/Dose-Rate Apoptosis

Different mechanisms of cytotoxicity appear to operate in different dose and dose-rate ranges for a given cell type. Indeed, several experimental studies support the tenet that LDR exposures tend to promote loss of clonogenic potential in some cell types (e.g., lymphomas) by activating apoptotic responses, whereas high doses tend to cause necrosis as their primary mechanism of cytotoxicity [10]. For example, low doses of EBRT induce substantial apoptosis in tumor cells and that the dose–response curve for apoptosis plateaus above ∼7.5 Gy [11]. Furthermore, multiple small fractions of EBRT were found to produce a higher level of apoptosis than a large single dose. Clinical effectiveness of lower doses of RNT and other LDR therapies could be related to their ability to optimize such effects, such as apoptosis exhibiting an inverse dose-rate effect [5].

Low-Dose Hyper-radiosensitivity–Increased Radioresistance

Many cell types exhibit an initial hypersensitive response at doses below ∼25 cGy, followed by a region of increasing radioresistance up to ∼50 cGy, the survival curve above 1 Gy closely following the expected LQ response [12]. This phenomenon, illustrated in Fig. 2, has become known as the “low-dose hyper-radiosensitivity–increased radioresistance” (LDH–IRR) response. The mechanism of LDH–IRR probably involves an alteration in the cellular processing of DNA damage as a function of dose. One possibility is that the transition from LDH to IRR may involve the activation of radioprotective DNA-repair pathways that are triggered by a certain threshold level of DNA damage. Cells would then be hypersensitive to low doses of radiation that produce insufficient DNA damage to trigger this protective process.
Fig. 2

Cellular survival responses of two normal human fibroblast strains, GM38 and GM10, following exposure to 60Co γ-radiation

LDH–IRR seems to be preferential and possibly limited to a fraction of cells in the G2 phase of the cell cycle, and an important consequence of the LDH–IRR response is that the conventional LQ model greatly underestimates cellular radiosensitivity after acute low doses. This limitation was addressed by Joiner et al. [12] in a modified LQ model that incorporates the impact of an induced repair threshold.

If the LDH–IRR response occurs also during LDR therapies, the latter could exert much greater cytotoxicity per unit of absorbed dose than would be predicted by the conventional LQ model. The LDH–IRR model leads to the prediction that DNA-repair processes should be less efficient after doses below the IRR threshold (i.e., typically ≤40 cGy) if this response is related to induced DNA repair.

G2 Synchronization, Bystander, and Cross-Fire Effects

In some tumor cell lines, LDR exposures in the range of 10–300 cGy/h have been shown to cause the partial synchronization of cells in the G2/M phase as a result of the prolonged activation of the G2 checkpoint [13]. This effect could have two consequences for LDR therapies. Firstly, it might abrogate the competitive effects of proliferation on the elimination of clonogenic tumor cells. Secondly, it might enhance the relative effectiveness of LDR radiation by holding the cells in G2, which is a relatively radiosensitive phase of the cell cycle, a mechanism that was invoked to explain the inverse dose-rate effect seen in some cell lines at LDR.

The “bystander” effect refers to the phenomenon whereby manifestations of damage (such as cell death) are observed in cells adjacent to those that are traversed by an ionizing particle but that are not themselves “hit” [5]. This means that a cytotoxic response in the presence of the bystander effect will be greater than that predicted on the basis of classical dosimetric estimates. The biological bystander effect appears to reflect the generation of a “damage signal” emanating from irradiated cells that is communicated to the nonirradiated adjacent cells through a variety of signaling mechanisms. These include intercellular cross talk, the release of reactive oxygen species (ROS) or of clastogenic factors, and intracellular signal transduction pathways. The contribution from these mechanisms probably varies among different model systems, leading to some controversy as to their relative importance.

The bystander effect is quite distinct from the cross-fire effect, another mechanism of RNT, in which an ionizing particle emanating from a source radionuclide in one cell deposits its energy in a distant target volume represented by a neighboring or distant cell [13]. Cross-fire effects depend predictably on the particle range and play a major role in the effectiveness of RNT using β-emitting isotopes such as those generated by 131I that have a range of millimeters in tissue. Such cross-fire effects with β-emitters are also important for therapeutic responses, because they should help to overcome the limitations imposed on RNT by heterogeneity in the distribution of the radiopharmaceutical within the tumor mass, which is especially important in solid tumor.

Adaptive Responses

The in vitro adaptive response is the phenomenon whereby exposure of cells to a low “priming” dose of radiation induces resistance to a subsequent higher-dose exposure [14]. Like LDH–IRR, the adaptive response has been suggested to involve inducible radioprotective mechanisms, such as DNA-repair pathways, although not all studies are consistent with such a mechanism. A possible explanation for these diverse findings is the broad range of cell types, assays, priming treatments, and times of observation employed in different studies; furthermore, adaptive responses typically occur only within a narrow dose range of ∼0.5–20 cGy. With respect to the potential role of adaptive responses in RNT, it has been noted that LDR irradiation can be regarded as a series of priming doses briefly separated in time; the adaptive response could, therefore, have a negative influence 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 to compensate for the anticipated heterogeneity of RNT dose distribution, which determines absent or suboptimal intratumoral radionuclide deposition, an event that is especially important in large, poorly vascularized tumors that contain regions of hypoxia [10]. The development of hypoxia in tumors is believed to represent a major barrier to successful EBRT, in part because hypoxic cells are ∼threefold resistant to acute exposures to ionizing radiation with respect to normoxygenated cells [15]. Conventional dose fractionation partially overcomes the negative effect of hypoxia, by allowing for the reoxygenation of hypoxic cells between fractions, and it is reasonable to assume that the same would be true for protracted LDR therapies. Under some conditions, fractionated delivery of radiolabeled antibodies and peptides has shown efficacy, with fractionated delivery causing less toxicity than a single administration. In general, both preclinical models and clinical radioimmunotherapy (RIT) evidence suggest that RNT fractionation results in a beneficial effect and in a more uniform radiation dose distribution. This has certainly proved to be an effective strategy with 131I-meta-iodobenzylguanidine (131I-MIBG), with obvious increases in clinical effectiveness, and there are now data to support the use of fractionated treatment with radiopeptides as a way of reducing toxicity.

Future Directions

There is no doubt that a better understanding of the radiobiology and mechanisms of action of RNT will facilitate the development of newer radiopharmaceuticals and the design of prospective phase III and IV clinical trials [5]. Although our understanding of the low-dose-related phenomena has increased dramatically in the last few years, it is important to validate these effects in the clinical setting. In particular, validation of a role for the bystander effect in RNT in vivo will impact the assessment of therapeutic response to RNT, as well as risk estimates for therapeutic and diagnostic radiopharmaceuticals. In addition, application of high-throughput genomic/proteomic screening methods (DNA arrays, single nucleotide polymorphism analysis, and protein arrays) will allow a rapid and accurate prediction of patient response, both in the tumor and in normal tissues [5]. Other issues, such as the role of metabolic markers in selecting therapies and dosage schedules, and the potential interactions between low-dose chemotherapy and RNT, constitute additional important areas for clinical development.

Dosimetry: Overview on Methods

The basic goal of RNT is to deliver enough radiation-absorbed dose to the tumor while minimizing the risk of toxicity to the bone marrow and to other normal tissues. For RNT, many physicians administer approximately the same activity to all patients, while ideally administered activity should be adjusted using a patient-specific treatment planning strategy based on radiation-absorbed dose. With a patient-specific approach, activity administration is optimized to maximize treatment efficacy while minimizing deleterious side effects to normal organs.

In RNT the absorbed dose is the energy deposited (E) per unit mass of matter (m) (with units of J/kg, 1 J/kg = 1 Gy). In RNT, E is the number of radionuclide disintegrations in a particular volume multiplied by the energy emitted per disintegration of the radionuclide and the fraction of emitted energy that is absorbed by a particular mass (m).

To improve the correlation between dose and the exposure effect, other quantities must be defined, such as relative biological effectiveness (RBE), radiation weighting factors, and tissue weighting factors. This suggests that energy absorbed per unit mass does not predict response at all levels, and some other factors must be considered.

Damage to cells is due primarily to indirect effects of radiation (formation of free radicals in water that diffuse and subsequently interact with cellular components, mostly DNA) and to some degree to direct effects (direct damage to DNA from radiation interaction). Also, different tissues and different individuals have different abilities to respond to and repair this damage. Thus, physical quantities such as the absorbed dose must be linked to radiobiological quantities to completely understand and be able to predict effects in a system.

Internal dose can be calculated by the following simple equation from the medical internal radiation dose (MIRD) Committee of the Society of Nuclear Medicine (SNM) [16, 17]:
$$ {D}_{\mathrm{T}-\mathrm{S}}=\frac{\overrightarrow{A}\times \Delta \times {\phi}_{\mathrm{T}-\mathrm{S}}}{M_{\mathrm{T}}}=\overrightarrow{A}\times S={A}_0\times \tau \times S $$
where D is the absorbed dose in a target organ (Gy), à is the cumulated activity in source region S, Δ is the energy emitted by the radionuclide per disintegration, \( {\phi}_{\mathrm{T}\to \mathrm{S}} \) is the fraction of energy emitted by the radionuclide in source region S that is absorbed in the target region, and MT is the mass of region T. Furthermore, τ is the residence time, which is simply equal to à /A0, the cumulated activity divided by the patient’s administered activity (A0). S is the absorbed dose per unit cumulated activity and it is given by
$$ S=\frac{\Delta \times {\phi}_{\mathrm{T}-\mathrm{S}}}{M_{\mathrm{T}}} $$
Equation 1 means that the absorbed dose depends on the half-life of the radionuclide and its spatial and temporal distribution in the target. The latter are typically obtained by images collected at different times after administration of the radiopharmaceutical and used to estimate the amount or concentration of radioactivity in a specific region. The level of activity obtained at different times after injection, plotted against time, gives a time–activity curve for a particular target, such as an organ or tissue. The integral of this curve gives the total number of disintegrations or the cumulated activity (Ã) for the region. Therefore, the main input data needed for evaluation of radiation dose are the biokinetic data that characterize the distribution and retention of the radiopharmaceutical throughout the biological system.
This absorbed dose could be used to estimate the biologic effective dose (BED) [18]:
$$ \mathrm{BED}= D\times \mathrm{R}\mathrm{E}\;\mathrm{where}\;\mathrm{R}\mathrm{E}=\left[1+\frac{D\lambda}{\left(\alpha /\beta \right)\left(\mu +\lambda \right)}\right] $$
where D is the absorbed dose, μ is the exponential repair rate constant that quantifies the rate of sublethal damage repair, and λ is the effective clearance rate constant (given by the sum of the physical decay and the biological clearance rate constants). It means that the BED may be defined as the product of the total physical dose D and a modifying factor named the relative effectiveness per unit dose, RE, that quantifies dose-rate effects with respect to radiosensitivity and repair of radiation damage.
The BED equation is derived from the linear-quadratic (LQ) model that describes the surviving fraction (Sf) of target cells after a radiation dose (D):
$$ {S}_{\mathrm{f}}= \exp \left(-\alpha D-\beta {D}^2\right) $$
where the linear component αD describes the DSBs induced by a single ionizing event, and the quadratic component βD2 describes the same effect induced by two separate ionizing events; α and β are the tissue-specific coefficients for radiation damage, α being proportional to dose (one single event is lethal) and β being proportional to squared dose (two sublethal events required for lethal damage). The α/β ratio is also named “repair capacity” and quantifies the sensitivity of a given tissue to changes in fractionation. Typical values for the α/β ratio are about 5–25 Gy for early-reacting normal tissues and tumors and about 2–5 Gy for late-responding normal tissues.

Also with the biological effective dose, the focus in radionuclide dosimetry study is to calculate the absolute amount of energy delivered per mass unit of tissue, i.e., the absorbed dose D.

In order to plan and design an appropriate dosimetric study, it is necessary to know approximately how the compound will be taken up and cleared from various organs and the whole body, by collecting multiple samples. Most therapeutic agents have a relatively fast phase of organ uptake and initial clearance, followed by more general systemic removal that lasts for many days. Therefore, a typical sampling scheme is to collect several samples in the first hours after administration and then about once or twice a day for a few days to several weeks.

To calculate the cumulated activity, the integral of the time–activity curve for each source organ may be obtained by (1) direct integration of data, for example, with the trapezoidal method, (2) a fit of the data to yield a mathematical expression of the uptake and retention in the target organ, and (3) using compartmental models, if the pharmacokinetics inside the target tissue is available.

Specific quantification techniques have been summarized for 2D and 3D imaging in the MIRD16 and MIRD 17 [19, 20]. Using planar data (2D imaging), the most accepted technique is to obtain images from the posterior and anterior projections and then correct the projected data in each region of interest (ROI) for attenuation and scatter. The most popular technique for attenuation correction involves the use of a Cobalt-57 (or other appropriate radionuclide) projection source imaged with and without the patient in the view, the attenuation coefficient for the system having been characterized in advance. For scatter correction, the two- or three-energy window method is widely accepted and applied when gamma camera software permits simultaneous acquisition in multiple energy windows. One of the best known packages able to offer mean absorbed doses in the organs, based on uniform activity distribution in organs/tissues, was the MIRDOSE3.1 package that implemented the use of whole-body MIRD-stylized mathematical phantoms representing adult males and females, children, and pregnant women [21]. The MIRDOSE3.1 software could be used for calculating internal dose for a large number of radiopharmaceuticals, the rapid comparison of calculations for different cases, examination of dose contributions to different organs, and regional marrow dose calculations.

MIRDOSE3.1 has been updated to a new generation code, Organ Level Internal Dose Assessment (OLINDA), employing the Java programming language and the Java Development Kit environment [22]. The entire code was rewritten, but all of the basic functions of the MIRDOSE code were retained, while others were extended. More individual organ phantoms were included, the number of radionuclides was significantly increased (including alpha emitters), and the ability to perform minor patient-specific adjustments to doses reported for the standard phantoms was made possible.

Quantitative 3D imaging using single-photon emission computed tomography (SPECT) methods is considerably more complex. The essential requirements for 3D imaging-based dosimetry are the availability of 3D anatomic imaging studies, such as CT or MRI, at least one 3D imaging study of the radioactivity distribution (e.g., PET or SPECT), and software that implements a point-kernel or Monte Carlo calculation methodology to estimate the spatial distribution of absorbed dose. Two fully developed packages are 3D-Internal Dosimetry (3D-ID) and DOSIMG [23, 24].

Clinical Experience

Clinical applications of dosimetry are not widely adopted in RNT, mainly because data from prospective randomized clinical trials that may prove the effectiveness of dosimetry in predicting clinical outcome after treatment are lacking. In order to prove that dosimetry-based RNT is of additional benefit over administration of fixed empirical activities or activities per body weight, prospective randomized phase III trials with appropriate endpoints should be undertaken [25]. So far, the lack of standardized methodology for calculating the absorbed doses and the continued use of approaches based on administrations of fixed empirical activities irrespective of personalized radiation dose estimates has hampered efforts to compare clinical outcomes in different patient populations and has led to significant difficulty in comparing results among different trials [4].

131I-Iodide Therapy of Differentiated Thyroid Carcinoma

Radioiodide therapy has largely been proven to be a safe and effective method in the treatment of patients with DTC after total or near-total thyroidectomy [26]. Nevertheless, although it has been shown to be useful for ablation of thyroid remnants and for treatment of locoregional or distant metastases, at present there is no consensus on the activity of 131I-iodide to administer, because of the lack of prospective, randomized data [27]. Many excellent reviews of empiric fixed prescribed activity have been previously published, and the most frequently used sets of empiric fixed prescribed activities range from 1.1 to 5.5 GBq for ablation to 5.5–11.0 GBq for treatment of metastases [28].

The advantages of using the empiric fixed prescribed activity are convenience, a long history of use, an acceptable rate and severity of complications, and the possibility to avoid the “stunning” phenomenon due to the diagnostic 131I-iodide activity [27].

However, the persistence of disease in a significant proportion of patients and the possibility for multiple small empiric activities to have less therapeutic benefit than the same total activity given at one time have led to attempts to improve such empiric approach to therapy [28].

Efforts to meet this goal have led to two basic dosimetrically determined prescribed activity approaches, each one addressing a different aspect of this problem. Benua et al. developed an approach to define the maximum activity of radioiodide that can be administered without significant bone marrow suppression [29]. Maxon developed a method to evaluate the activity of radioiodide needed to adequately treat metastatic lymph nodes [30].

The limited bone marrow toxicity method (Benua approach) was developed at the Memorial Sloan Kettering Cancer Center, by setting an upper limit for the radiation dose to the patient’s blood, which is considered as a surrogate for the critical organ, i.e., the red bone marrow [29].

Since radioiodide concentration is almost identical in blood as in inner organs including the red bone marrow, assessing the blood absorbed dose allows to estimate the radiation-absorbed dose that will be delivered to the hematopoietic system of the individual patient during therapy [30]. A summary of the methodologies used can be found in the review article by van Nostrand [28] and in the guidelines of the Dosimetry Committee of the European Association of Nuclear Medicine (EANM) for pre-therapeutic dosimetry [31].

The method allows estimation of the radiation dose that will be delivered to the hematopoietic system per unit activity administered to a given patient and restricts such dose to no more than 2 Gy to the blood [29, 31]. Therefore, the maximum activity for treatment is calculated as the amount of 131I-iodide that would deliver an absorbed dose of 2 Gy to the blood compartment [32].

This method requires evaluation of the kinetics of activity in the blood and in the whole body, obtained by conjugate views of a whole-body scan (WBS) acquired with a dual-head gamma camera equipped with high-energy collimators [28].

To evaluate the blood kinetics, five blood samples should be obtained over 1 week (e.g., at 2, 6, 24, 96, and 144 h) after administration of 131I-iodide, and the blood activity should be measured in a calibrated well counter from aliquots of blood samples [28].

The first WBS measurement obtained 2 h after tracer administration represents 100% of administered activity, while measurements are repeated at 24, 48, 72, and 96 h (or later if uptake and/or renal clearance is delayed). As an alternative to WBS conjugate-view imaging obtained with a gamma camera, measurements with an external probe can be used [28].

To calculate the whole-body activity as a function of time and circulating activity per mL of blood, the geometric mean of corresponding net counts obtained by conjugate views and all blood activities are normalized to the first data point and to the administered activity, respectively [28, 31].

The curves, A(t), describing the activity in the blood and in the total body as a function of time after the administration are usually multi-exponential, and bi-exponential fitting is usually appropriate to determine the function describing time–activity curves in the blood and in the total body, respectively.

The residence times in the whole body and activity concentration in blood, τTotalBody[h] and τBlood[h], are calculated by integrating the corresponding retention function R(t) = A(t)/A0.

According to the generally accepted MIRD formalism, the mean absorbed dose to the blood per unit administered activity is determined by the sum of contributions of blood self-irradiation and of penetrating radiation from the whole body.

The mean blood absorbed dose per unit administered tracer activity can therefore be calculated as
$$ \frac{{\overline{D}}_{\mathrm{Blood}}}{A_0}\left[\frac{\mathrm{Gy}}{{\mathrm{GB}}_{\mathrm{q}}}\right]=108\times {\tau}_{\mathrm{Blood}}\left[ h\right]+\frac{0.0188}{\mathrm{wt}\left[\mathrm{kg}\right]}\times {\tau}_{\mathrm{TotalBody}}\left[\mathrm{h}\right] $$
The activity to be administered for a blood absorbed dose of 2 Gy is
$$ {A}_{\mathrm{Adm}}\left[{\mathrm{GB}}_{\mathrm{q}}\right]=\frac{2\times {A}_0\left[\mathrm{Gy}/\mathrm{GBq}\right]}{D_{\mathrm{Blood}}} $$
Under the conservative assumption that the activity concentrations within the hematopoietic tissue and the blood are identical [33], a red marrow-based approach for the determination of the maximum activity to be administered has been proposed [33]. Although this method seems to be accurate, no systematic clinical validation of the red marrow absorbed dose versus toxic effect has yet been undertaken.
The limited bone marrow dosimetry is easy to perform both pre-therapeutically and peri-therapeutically, thus allowing administration of additional activity for selected patients without risk of severe side effects. However, the original method might not to be applied in the presence of extended metastatic bone involvement, as the blood-based absorbed dose calculation could underestimate the absorbed dose to the red marrow. Similarly, it should be carefully applied also in the case of patients with diffuse lung micrometastases, because the critical organ could be the lung itself instead of the hematopoietic red marrow [34, 35]. The main limitations of this method are reported in Table 1.
Table 1

Problems and difficulties of limited bone marrow dosimetry (Benua approach)

No valid clinical data or outcome rates yet exist on a benefit of the strategy

The approach does not estimate the absorbed dose to the thyroid remnant or metastasis

“Stunning effect” due to diagnostic activity of 131I could alter lesion biokinetics and the absorbed dose in a subsequent 131I therapy

Increased cost and practical inconvenience

The goal of the lesion-based dosimetry (Maxon approach) is to individualize radioiodide activity that delivers the recommended absorbed doses to ablate thyroid remnant or to treat metastatic disease while minimizing the risk to the patient [36]. These absorbed doses are traditionally considered to be ≥300 Gy to ablate thyroid remnant and ≥80 Gy to successfully treat metastatic disease [36].

In order to determine the activity required to deliver the absorbed doses, it is necessary to measure the uptake, clearance, and concentration of 131I contained in the identifiable thyroid remnants and/or metastases. One way to ascertain these parameters is through an analysis of selected regions of interest (ROIs) on conjugate-view gamma camera images or on SPECT images, obtained at sequential time points after administration of a tracer activity. Typically, these images should be acquired at 24, 48,72, and 96 h after tracer administration, but later time sampling might be necessary if the uptake and clearance are delayed. In addition, transmission images to correct for attenuation in the lesion area, scatter images, as well as calibration procedures are necessary. A curve-fitting procedure is then employed to determine the assumed single-exponential half-life value and to extrapolate the curve to zero time to determine the initial activity in the lesion [28].

Pre-therapeutic dosimetric assessments of the activity required to achieve a certain prescribed absorbed dose to a remnant or lesion are often based on adaptations of the generic MIRD equation for absorbed dose, as previously described:
$$ \overline{D}=\overrightarrow{A}\times S $$
where \( \overline{D} \) denotes the mean absorbed dose to the remnant/lesion, Ã is the cumulative activity, and S is the “S factor” of the MIRD scheme depending on the lesion/remnant mass.

For dosimetry of metastases, CT, MRI, or US can be used for attenuation correction and to determine the mass, while no thoroughly validated method is yet available for ablative treatments to exactly calculate the thyroid remnant volume after surgery.

If the lesions are small, the “nodule module” of the OLINDA/EXM software might be useful to generate a spherical model of the remnant and/or tumor. Furthermore, if the size of the lesion is smaller than 5.0 mm (assuming that such small size can actually be accurately determined), then the tissue range of the beta particles can no longer be neglected in the dose calculation. This as well as other limitations of the lesion-based method is reported in Table 2.
Table 2

Problems and difficulties of lesion-based dosimetry (Maxon approach)

Not uniform absorbed doses within each lesion

An accurate estimate of the lesion mass is not always possible

Low uptake in lesions and, therefore, low count rates may cause statistical errors in the measurements

The biological effectiveness of dosimetry-guided 131I therapy is not proven yet

“Stunning effect” due to diagnostic activity of 131I could alter lesion biokinetics and the absorbed dose in a subsequent 131I therapy

Conventional radiopharmaceuticals that allow quantitation of radioiodide uptake in thyroid remnants and metastases, such as 123I-iodide or 131I-iodide, have limitations; in fact, there are problems regarding cost and the logistics of supply for 123I-iodide, while 131I-iodide has poor imaging properties (that translate into relatively low sensitivity) and its use can cause the so-called “stunning” phenomenon [27]. In contrast, with the introduction of hybrid positron emission tomography/computed tomography (PET/CT) devices to the clinic, 124I PET/CT is becoming an emerging and attractive methodology for lesion dosimetry in the management of patients with DTC [37]. With its ability to determine the concentration of 124I-iodide at anatomical sites of interest, PET/CT provides quantitative images and provides higher spatial resolution and imaging sensitivity than gamma camera-based devices [37].

Using the PET data as input to a fully three-dimensional dose planning program, Sgouros et al. [38] calculated spatial distributions of absorbed doses, isodose contours, dose–volume histograms, and mean absorbed dose estimates for a total of 56 tumors. The mean tumor-absorbed dose for each patient ranged widely, from 1.2 to 540 Gy, while distribution of values for the absorbed dose in individual tumor voxels was even more dispersed, ranging from 0.3 to 4,000 Gy.

Median per patient tumor radiation-absorbed doses between 1.3 and 368 Gy were reported by de Keizer et al. [39], who performed tumor dosimetry after rhTSH stimulated 131I-iodide treatment. Dosimetric calculations were performed using tumor radioiodide uptake measurements from posttreatment 131I scans, while tumor volumes were estimated from radiological images.

In general, a 124I PET/CT dosimetry protocol involves estimating the absorbed dose per administered 131I activity for each radioiodine-positive lesion, allowing the calculation and the choice of the actual recommended 131I activity. However, pre-therapeutic 124I PET/CT dosimetry requires the knowledge of lesion volumes in order to adequately correct for partial volume effects. Such effects can reduce measured activity concentrations in lesions by up to ~three times the spatial system resolution, i.e., up to ~2 cm in diameter.

Often no morphological CT correlates can be assigned to 124I PET foci. This can be partially attributed to the fact that CT examinations prior to radioiodine therapy need to be performed without contrast media to avoid iodine contamination. If no CT correlates exist, the target volumes must then be assessed from PET images alone by applying various threshold methods. The original 124I PET dosimetry protocol entailed five PET measurements at 4, 24, 48, 72, and 96 h after 124I administration, although simplified models by using four, three or two points (24 h/96 h) have been proposed [40].

There are only a few published studies that have examined the absorbed dose in thyroid remnants and metastases using 124I PET/CT. Freudenberg et al. [41] determined a median LDpA of 95 Gy/GBq for bone metastases (n = 73), 113 Gy/GBq for lymph node metastases (n = 32), and 86 Gy/GBq (n = 14) for lung metastases in those patients who were eligible for RIT.

At the moment, considering the slow progression disease and long follow-up period, it is difficult both to evaluate the long-term benefits and to design classical blinded and randomized studies in DTC patients submitted to pre-therapy 124I PET/CT dosimetry. However, pre-therapy 124I PET/CT dosimetry seems to be very useful in selected patients with locoregional or distant metastases who may benefit from radioiodine therapy with an individually tailored escalated activity or to abandon the therapy because of insufficient obtainable dose in the lesions.

Besides being a promising method to obtain accurate dosimetry in patients with metastases, 124I PET/CT imaging is a useful diagnostic tool for accurate pre-radioiodine therapy staging, with a diagnostic accuracy similar to the WBS obtained after high therapeutic activities of radioiodine.

Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) represents a promising option for patients with somatostatin receptor-expressing tumors. Several clinical trials have proven its efficacy, especially for neuroendocrine tumors [42, 43]. However, possible radiation-induced renal damage and large inter-patients’ variability in biodistribution and tumor uptake require accurate dosimetry-based therapy planning. Recent improvements in dosimetry methods [44, 45, 46, 47, 48, 49, 50, 51] and radiobiological models [18, 52, 53] have resulted in promising results and correlations that constitute challenging perspectives for optimized PRRT and for other radionuclide therapies as well [53, 54, 55, 56, 57].

90Y-DOTATOC, 90Y-DOTATATE, and 177Lu-DOTATATE are the most widely employed radiopharmaceuticals for PRRT. Pilot trials also considered 111In-octreotide for therapy, due to the high LET of its Auger-electron emission. However, since tumor response was seldom achieved, 111In-based PRRT protocols have virtually been abandoned [42].

The physical half-life of 90Y is compatible with the peptide kinetics, while the high energy of the β-particles confers high probability of killing all neoplastic cells in a certain volume around the uptake site through the cross-fire effect. Conversely, 90Y is not easily suitable for imaging due to the lack of γ-emission, even if promising results have been shown for planar and SPECT bremsstrahlung 90Y-images corrected for scatter and detector response, either based on Monte Carlo simulations or obtained by new-generation equipments (SPECT/CT) [58, 59, 60]. The possibility to obtain 90Y-PET images due to the low incidence of pair production of 90Y (branching ratio of 32 × 10−6) is also challenging. It has already found application in the radioembolization of liver lesions using 90Y-microspheres [61, 62] and has been recently studied to be applied in 90Y-PRRT [63].

111In-octreotide, 86Y-octreotide, and 68Ga-peptides have been proposed as alternative options to 90Y-imaging. Due to their similar chemical characteristics, the assumption of comparable behavior in vivo of 111In- and 90Y-derivatives has been widely accepted [64]. Thus, several authors have used the identical molecule labeled with either 111In or 90Y for imaging or for therapy, respectively (e.g., 111In-DOTATOC and 90Y-DOTATOC). Since the physical T1/2 of 111In is almost identical to that of 90Y and is compatible with the distribution kinetics of peptides, the diagnostic activities usually administered (~185 MBq) allow one to obtain serial images (planar, SPECT) over 3–4 days, although some difference in the chemical structure of 111In-octreotide cannot offer identical biokinetics of the corresponding 90Y-conjugate. A fortiori, even less recommendable is a dosimetry plan based on the distribution of 111In-octreotide (Octreoscan©), even though some authors claim its use for a “practical” dosimetry [65, 66]. The same compound labeled with 86Y (86Y-DOTATOC) represents a further option, since it totally preserves the chemical nature of 90Y-derivatives and offers PET resolution. However, limitations of this approach are due to the physical T1/2 of 86Y (14.7 h, too short to follow the kinetics of uptake peptide and retention), complex image quantification, cost, and poor availability [64]. Similarly, 68Ga-peptides are not suitable for dosimetry purposes, despite the high-quality PET images provided, because of the extremely short T1/2 of 68Ga (68 min) as compared to the kinetic pattern of peptide distribution. Furthermore, the chemical properties of 68Ga might slightly alter the biodistribution kinetics of the radiolabeled peptide as compared to the therapeutic agent [64].

In comparison with 90Y, 177Lu induces less damage by cross-fire effect, but releases higher energy in smaller tissues. Moreover, the γ-rays emitted by 177Lu are suitable for imaging and dosimetry, although for proper scintigraphic imaging, diagnostic/dosimetric activities of at least of 370–740 MBq should be administered. Most often dosimetry is evaluated after administering therapeutic activities of 177Lu-DOTATATE (i.e., 3.7–7.4 GBq), as treatment is usually given in multiple cycles. So, the activity to be administered in cycles after dosimetry can, in case, be adjusted based on the dosimetry results.

90Y- and 177Lu-peptides have shown similar biological half-lives for organs and lesions, with varying uptakes depending on the different expressions of somatostatin receptors with respect to the peptide affinity. The same dosimetry methods and time schedules for data recording can be used for 90Y- and 177Lu-PRRT, but dosimetry must be assessed specifically for every used radiopeptide, and for the single patient, due to wide intra-patient variations as well as frequent inter-patient differences on tumor uptake.

The absorbed doses per unit activity for 177Lu-peptides are much lower (two- to fourfold) than for 90Y-peptides [64]. The activities administered in 177Lu- or 90Y-PRRT should vary accordingly, although the therapeutic protocols most commonly employed in clinical studies are not yet uniformly established with respect to activities administered and number of cycles [67, 68, 69].

Table 3 reports a summary of the dosimetric results for the most commonly used 90Y- and 177Lu-peptides (90Y-DOTATOC and 177Lu-DOTATATE), which share some properties: (1) the pharmacokinetics are characterized by very fast blood clearance and urinary elimination, leading to low exposure of the whole body (Fig. 3); (2) the spleen, kidneys, and liver receive the highest absorbed doses; (3) the kidneys are the dose-limiting organs; and (4) no significant uptake in bone or red marrow is typically reported.
Table 3

Absorbed dose estimates for the principle PRRT trials with 90Y-DOTATOC and 177Lu-DOTATATE


Absorbed doses per unit activity (Gy/GBq) mean values among patients published by different authors




Red marrow

0.03; 0.06; 0.09; 0.17

0.02; 0.04; 0.07


1.71; 2.44; 2.73; 3.84

0.62; 0.81; 0.88; 0.97


0.27; 0.66; 0.75; 0.86; 0.92

0.13; 0.18; 0.21


2.19; 4.74; 5.36; 7.20

0.64; 1.2; 2.15


1.04; 1.59; 2.61


Total body

0.10; 0.15; 0.28



(1.4–31); (2.1–30); (2.4–42)

(0.6–56); (3.9–38)

Adapted from Cremonesi et al. [64], with permission

aAbsorbed dose values reported include renal protection

bFor tumors, instead of the mean values, the ranges of variability are presented

Fig. 3

Radiopeptides blood clearance (red curve) and urine excretion (blue dotted curve)

To reduce renal radiation burden, preclinical and clinical studies showed that the infusion of protective agents (negatively charged amino acids) allows 25–65% reduction of the kidney uptake [70]. Despite such protection, the cumulative dose to the kidneys could still be borderline with the limits considered for nephropathy induction, especially with 90Y-peptides.

Increased application of PRRT has stimulated interest in improving calculation of the radiation burden to organs at risk. There are two remarkable studies by Sandstrom et al. that focus on individualized kidney and bone marrow dosimetry and on the method dependence, observer variability, and kidney volumes of dosimetry for 177Lu-PRRT [48, 49]. Some papers use SPECT/CT-based renal dosimetry in 177Lu-PRRT [50, 51], while an accurate method for planar image activity quantification and absorbed dose assessment in general is described by the group of Sjögreen et al. The clinical value of the absorbed dose to the kidney is the topic discussed by Swärd et al. [45].

Two papers compared planar and SPECT images of 177Lu-PRRT, both considering planar images corrected for scatter, background, attenuation, and response of the system, and SPECT images corrected for attenuation and response of the system. The first, by Garkavij [44], observed ~10% difference in the dosimetric results for the kidneys when comparing planar images using two different background corrections, ~20% difference when comparing planar with SPECT images, and ~10% difference when comparing the hybrid method using SPECT combined to planar images with the 3D SPECT method. The second, by Sandström [67], obtained a difference within 14% for the kidneys when comparing SPECT vs. planar images, while a difference within 10% for kidneys up to 23% for the liver when comparing two different 3D methods to draw the volumes of interest.

Other comparisons were made by Larsson et al. who focused on different planar dosimetric methods for the kidneys and studied the influence of the number of time points and the use of standard organ sizes. The authors found a large interindividual variation – which increased in case of the lack of late acquisition on day 7 – and demonstrated the need of personalized dosimetry and treatment planning [47]. Guerriero et al. further increased the accuracy of the biokinetics of kidneys and tumors in both, 177Lu- and 90Y-peptide therapy. They investigated the most adequate timing for imaging and interpolation of the time–activity curve, the performance of a simplified dosimetry by means of only one to two scans, and the influence of renal risk factors and different peptides (DOTATOC vs. DOTATATE) [71]. The trapezoidal method followed by physical or biological decay after experimental data was compared with mono- and bi-exponential fits, skipping or not the 6 h and the 3-day time points. The authors found that data should be collected at least up to ~100 h for 177Lu therapy and ~70 h for 90Y therapy in order to minimize dose uncertainties.

Another important issue for biokinetics is the possible variation among cycles. The study by Garkavij et al. compared dosimetry to the same patients in different cycles and showed that the first two of the four planned therapy cycles make the major contribution to the tumor-absorbed dose, possibly due to a saturation of the peptide receptors, while the different cycles contribute on average equally, within 10%, to the absorbed dose to the kidneys [44]. These findings apply in general and have been confirmed by other investigations [57], but there is a minority of cases in which the tumor is so avid of radiopeptides that it sequesters a very high percentage of the injected activity, leading to a so-called sink effect that decreases the activity concentration in healthy organs including the kidneys. In such cases, if the tumor is responsive during the course of therapy, the biokinetics in subsequent cycles may vary consistently, and dosimetry at a certain cycle is no more representative of the other cycles and not useful to estimate the cumulative doses to organs at risk and tumor [72].

In the attempt to improve accuracy of renal dosimetry estimates, the standard methods that assume uniform activity distribution in kidneys have been shifted to the multi-region MIRD model for a sub-organ kidney dosimetry and dose-rate effects [22, 55, 73, 74]. Some authors proposed the analysis of SPECT images to assign activity to the cortex or to the medulla for a patient-specific dosimetry [66]. In truth, the resolution of SPECT images is unable to provide a reliable activity distribution within the kidney substructures, being too low as compared to the 1–3 mm thickness of the cortex, for instance. More detailed information on intrarenal distribution has been derived instead from experimental results of renal autoradiograms [75].

The impact of the physical characteristics of the radionuclides with respect to inhomogeneous activity distribution (also within sub-organ regions) is a 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 TD50 value derived from the EBRT) of 44 Gy were found for 90Y-PRRT [55]. Besides the most relevant impact on PRRT, these findings have shown the great potential of sharing information from different radiation release modalities. As a further support for the radiobiological model, clinical experience has shown that multiple-cycle protocols lower the nephrotoxicity, while patients with higher BED values and more serious side effects to the kidneys received the treatment in a few cycles [69, 76, 77]. This observation perfectly matches with the theoretical expectation from the BED concept: for a given cumulative dose, the higher the number of cycles, the lower the total BED, thus the lower the damage [69, 78]. Clinical results on 90Y-PRRT have provided evidence of the safety up to a BED of about 40 Gy to the kidneys, cumulatively, and that risk factors (such as hypertension and diabetes) lower the tolerability to a BED of about 28 Gy [55, 76].

Treatment protocols based on multiple therapy cycles represent a useful modality to lower toxicity for a same cumulative activity, and/or improve the therapeutic outcome for a same fixed BED to the kidneys, owing to the different radiosensitivity of most tumors versus the kidney tissue. Cycles seemed especially effective in 90Y-PRRT, where frequent occurrence of renal impairment has been clinically confirmed [69, 76, 79].

90Y-peptides appear to be less nephrotoxic [43, 80, 81]. Possible reasons for these different outcomes are the different particle ranges in tissues and different peptide localizations. The short-range β-particles of 177Lu-peptides, or the Auger electrons of 177Lu-peptides, might irradiate the tubuli (radioresistant cells) more selectively while the long-range β-particles of 90Y-peptides may increase the irradiation of the more radiosensitive glomeruli, with consequent higher toxicity [69, 75, 78]. On the other hand, the advantage of cycling PRRT with 177Lu is not as important with 90Y. This is clear when considering that the contribution to the cumulative absorbed dose to the tumor after each therapy cycle gradually decreases [44] and that the absorbed dose to the kidneys with 177Lu-PRRT is much lower at the activities usually administered in clinical trials, leading to a lower risk of nephrotoxicity. Overall, the use of too many cycles is not recommendable for 177Lu-PRRT, while four cycles or possibly less seem to offer a better chance to avoid repair of sublethal cell damage and repopulation without dramatically alter the renal risks.

Despite long-term data analysis of 90Y-trials and 177Lu-trials, the intrinsic toxicity of the two radiopeptides is still to uncertain [64, 77, 82, 83]. Because the 177Lu-based and the 90Y-based clinical protocols use fixed total activities (e.g., 177Lu, four cycles of 7.4 GBq; 90Y, three cycles of 3.7 GBq) that lead to lower kidney absorbed dose and BED values for 177Lu-schemes as compared with 90Y. A reliable comparison of 177Lu- vs. 90Y-peptide therapy would require randomized trials conceived to release the same absorbed dose or BED using different radiopeptides. The choice of the most suitable radiopharmaceutical can be made based on individual differences in tumor mass and location, adjacent tissues, and targeting compound affinity. In principle, the physical characteristics of 177Lu, with lower tissue penetration, make it more suitable for small tumors and micrometastases, while the cross-fire effect 90Y might have the advantage of a higher radiation burden to larger lesions [64]. This hypothesis has been supported by preclinical findings and is the basis for new clinical rationales proposing cocktails of 177Lu- and 90Y-radiopeptides. New interesting approaches propose tandem treatments with 90Y- and 177Lu-peptides, with equal or different administered activities of the two radiopharmaceuticals [84, 85].

For tumor response, a first remarkable correlation has been observed between tumor-absorbed dose and tumor reduction with 90Y-DOTATOC [65]. Responding tumors could be identified as those receiving much higher doses compared to nonresponding (up to sixfold, ~230 vs. ~40 Gy). Moreover, when correlating tumor-absorbed dose versus lesion mass reduction, a trend versus a dose–effect relationship was found, although not statistically significant, with a correlation coefficient of 0.5.

Excellent correlations were obtained between absorbed doses and tumor volume reduction after 177Lu therapy, with a correlation coefficient of 0.6 for tumors bigger than 2.2 cm and a correlation coefficient of 0.9 in tumors bigger than 4 cm. These results were obtained by the improvement of dosimetry methods, namely, by correcting for the partial volume of the lesions identified in SPECT images [57].

Many parameters may influence the response of tumors – such as tumor dimension, vascularization, radiosensitivity, and activity distribution. Larger series of data with specific radiobiological parameters for different tumor characteristics are to be collected and will certainly improve outcome prediction.

Studies have measured circulating NET tumor transcripts (NETest), based on several marker genes to monitor tumor gene activity levels. The results confirmed that this test provides assessment of disease status and treatment effectiveness with significantly higher accuracy and earlier time points as compared with other biomarkers (such as cromogranine A) and morphological/functional imaging [86, 87]. It is quite clear that interdisciplinarity including dosimetry and genetic profile will play a crucial role in radionuclide therapies, allowing identification of patients that are not likely to be responsive and/or patients with a low risk of adverse sequelae, guiding trials, and tailoring therapies.

Radioimmunotherapy of Lymphoma

Radioimmunotherapy (RIT) offers an important option for the treatment of follicular low-grade non-Hodgkin’s lymphoma (NHL) refractory or relapsed after treatment with the current best practice [88]. Two radiolabeled antibodies are commercially available for treatment, tositumomab and ibritumomab, that are the radiolabeled immunoglobulin components of Bexxar and Zevalin, respectively [88, 89].

Bexxar is the 131I-labeled anti-CD20 antibody tositumomab, while Zevalin is the 90Y-labeled anti-CD20 antibody ibritumomab. Although both tositumomab and ibritumomab recognize the same epitope CD20 (one of many epitopes expressed on the mature B cell), they have slightly different binding characteristics [88].

For both radiopharmaceuticals, an unlabeled antibody is infused before administration of the radiolabeled murine anti-CD20 antibody component. In the Bexxar regimen, both the labeled and unlabeled antibody are tositumomab. In the Zevalin regimen, the unlabeled antibody is rituximab (the chimeric antibody used as an immunotherapeutic and marketed as Rituxan), while the labeled antibody is ibritumomab [88, 89].

In Europe only Zevalin is commercially available, while in the USA and Canada, both Zevalin and Bexxar have been approved for clinical use [88].

No direct comparison in a randomized blinded trial has been performed to assess whether the difference in physical characteristics of the two radionuclides, 131I and 90Y, have different therapeutic effects or toxicity.

In principle, the greater energy of the β emitted by 90Y is thought to be advantageous in the therapy of larger tumor masses, whereas the lower energy of the 131I-particle emission is thought to be an advantage for treating patients with small tumor foci and marrow involvement. In the non-myeloablative setting, the use of either agent is contraindicated for patients with lymphomatous infiltration exceeding 25% of the bone marrow [90].

For Bexxar and Zevalin, different protocols and dose determinations have been reported, also due to the different approval requirements by regulatory agencies in the USA and Europe. However, for both radiopharmaceuticals, the red bone marrow is the dose-limiting organ due to its intrinsic radiosensitivity, to the rapid equilibration of the radiolabeled antibodies within its extracellular fluid volume, and to the long retention kinetics in the bone marrow [88].

When using Bexxar, dosimetry is estimated to determine the whole-body radiation-absorbed dose, since hematological toxicity and the dose–clinical response relationship depend on the whole-body radiation-absorbed dose rather than on a MBq/kg dosing schedule [91].

The optimal clinical benefit with acceptable hematological toxicity has been observed at 65–75-cGy whole-body radiation-absorbed dose, considering 65 cGy for patients with platelet counts between 100,000 and 150,000 and 75 cGy for patients with platelet counts greater than 150,000 [88].

The whole-body radiation-absorbed dose is determined from three WBS acquisitions after the administration of 185 MBq of 131I-tositumomab (with prior infusion of 450 mg of unlabeled tositumomab), administered for determining the residence time which is necessary for dosimetric estimates.

The purpose of the scan is simply to evaluate the whole-body total counts rather than to produce a diagnostic image, because the parameters involved in visualizing a tumor (dose administered, tumor size, and location) are different from those involved in radiobiological response evaluations [88].

Whole-body counts are determined from the total counts on the anterior and posterior WBS acquired 1 h postinjection (day 0), then 2 days (day 2) and 5 days (day 5) later, to determine the radiopharmaceutical residence time (τ) and cumulated activity (Ã) in the body.

To calculate the desired therapeutic activity, the following equation can be used:
$$ \mathrm{Theraputic}\;\mathrm{dose}=\frac{\overrightarrow{A}}{\tau}\frac{\mathrm{Desired}\;\mathrm{TBD}\left(\mathrm{cGy}\right)}{75\mathrm{cGY}} $$

The calculation simply divides a cumulated activity, Ã (tabulated for several patient’s weight), that would result in the patient receiving a 75-cGy whole-body radiation-absorbed dose, by the patient-specific residence time, τ. This would result in the activity associated to a 75-cGy whole-body absorbed dose that could be also rescaled by an absorbed 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 tositumomab followed by 131I-tositumomab) is repeated with the 131I-tositumomab therapeutic activity (1.85–5.5 GBq) that had been determined by dosimetry (Table 4).
Table 4

Organ radiation absorbed doses (mGy/MBq) for 90Y-ibritumomab tiuxetan (Zevalin®), based on pre-therapeutic 111In imaging


Number of patients

Median and range (mGy/MBq)



7.35 (0.37–29.7)



4.32 (0.85–17.5)



2.05 (0.59–4.86)

Red marrow (blood derived)


0.59 (0.09–1.84)

Red marrow (sacrum derived)





0.22 (0–0.95)  

Bone surfaces


0.53 (0.09–1.31)

Urinary bladder wall


0.89 (0.38–2.32)

Other organs


0.41 (0.06–0.62)

Total body


0.54 (0.27–0.78)

In the USA and EU countries, biodistribution studies are not required because of the lack of correlation between red marrow dose and toxicity and considering that red marrow toxicity is reversible. This choice (which seems to be dictated mainly by practical/economical reasons) is arguable, as cases in which only the scintigraphic images were able to predict toxicity of the treatment are not so rare [92]. However, when using larger activities in clinical trials involving myeloablative doses with stem cell transplantation, personalized dosimetry estimates are required to avoid unpredictable toxicity. In fact, with bone marrow rescue, it is not possible to identify a priori a “safe” maximal activity or a unique critical organ for all patients, because of the wide intra-patient variability in doses to the vital organs.

At present, neither 90Y-ibritumomab tiuxetan dosimetry outcomes in favor of its predictivity have been found nor correlation between red marrow dose and hematological toxicity has been demonstrated [91, 93, 94, 95, 96]. This consideration has discouraged the practice of red marrow dosimetry for Zevalin. In this regard, toxicity in these patients is most likely linked to involvement of bone marrow by the disease and to reduced bone marrow reserve due to previous aggressive chemotherapy regimens [97].

The therapeutic activity of Zevalin for the non-myeloablative therapy of rituximab-refractory or relapsed patients with low-grade follicular non-Hodgkin’s lymphoma is prescribed proportionally to the patient’s weight, with recommended administered activity of 15 MBq/kg up to a maximum limit of 1,200 MBq [94]. Patients with platelet counts between 100,000 and 150,000 should receive 11 MBq/kg [94]. Much higher activities, ranging from 29 to 55 MBq/kg, have been used under myeloablative regimens, followed by autologous stem cell transplantation (ASCT) [98].

Radioembolization of Liver Tumors

Trans-arterial radioembolization (TARE) is a locoregional treatment developed in order to release high radiation doses to malignant hepatic lesions by intra-arterial administration of a radiation vehicle. The rationale is the same as for trans-arterial chemoembolization (TACE): liver tumors are mainly fed by arterial blood, while normal tissue by portal blood. TARE consists of the intra-arterial administration of a radioactive agent. This is permanently trapped in the microcapillaries where it delivers its radiation until complete physical decay. In the last decade, significant response rates have been achieved with this approach in patients with unresectable primary hepatocarcinoma (HCC) [99] or secondary hepatic malignancies [100].

Several techniques have been tested in research trials, including the administration of radiolabeled molecules (such as 90Y-,131I-,188Re-,166Ho-Lipiodol) or of microspheres loaded with radionuclides (e.g., 90Y, 166Ho), differing in size, material, and specific radioactivity. However, the impressive increase in the number of treated patients in the last decade follows the registration of only two medical devices, i.e., microspheres loaded with 90Y: (1) SIR-Spheres made in plastic resin (Sirtex Medical, Lane Cove, Australia) and (2) TheraSphere made in glass (MDS Nordion, Ottawa, Canada). The main difference between the two products is the number of administered particles, which is ten times higher for resin particles. This implies a truly embolic behavior, never observed in glass microspheres. The second difference is the approved indication in the USA versus Europe. The FDA approved the use of resin spheres in patients with colorectal carcinoma metastatic to the liver, while glass spheres in HCC patients with or without portal vein thrombosis. In Europe and in various countries worldwide, both agents have regulatory approval for liver neoplasia.

The amount of activity to be administered should generally be established taking into account the clinical and dosimetric factors which affect the outcome: basal liver function (Child-Pugh score, presence of portal vein thrombosis, previous or concomitant treatment), tumor burden, targeted organ fraction, predicted absorbed dose to normal tissue, and absorbed dose to lesions. Actually in Europe, the Council Directive 2013/59 in Article 56 prescribes that any radiation treatment be optimized using dosimetry. In practice, the choice of the injected activity has been based on empirical approaches or on rough dosimetric evaluations, as summarized hereinafter.

For both devices, therapy is generally simulated by intra-arterially administered 99mTc-albumin macroaggregates (99mTc-MAA), in order to evaluate possible shunting to the lungs (lung shunt fraction, LSF), which limits the administrable activity, or avoid gastrointestinal (GI) shunt, which is an absolute contraindication to treatment. A planar trunk scintigram and a liver SPECT scan are usually accomplished. A major advantage deriving from the permanent trapping is that, differently from all other radiopharmaceuticals, images can be quantitatively analyzed to perform dosimetric evaluation though taken at only one time point. The adequacy of 99mTc-MAA for simulation is under discussion. Although similar distribution patterns of 99mTc-MAA and bremsstrahlung 90Y-microsphere images have been generally reported, some dissimilarities have also been observed, possibly due to the different size and number of MAA versus microspheres or to occasional alterations of the original vascular anatomy produced by angiography [101]. Nevertheless, the acquisition of pre-therapeutic images represents a suitable source of clinical and dosimetric information for risk/benefit evaluation, through a treatment planning session similar to that ordinarily performed in external beam radiotherapy. Post-therapy images can be obtained either as bremsstrahlung SPECT or as 90Y-PET. The latter are by far more accurate from the quantitative point of view. Post-therapy imaging has almost the same level of importance as the 99mTc-MAA scan, since it demonstrates the real therapeutic biodistribution.

Patient-specific dosimetry requires a detailed slice-by-slice volume of interest (VOI) drawing around tumor (T) and non-tumor tissue (NT). Using the mean dose approach, values of the absorbed doses per unit activity can easily be derived from two simple equations. The first is the way to convert counts in the image in 90Y activity:
$$ {A}_{\mathrm{VOI}}\left({}^{90} Y\right):{A}_{\mathrm{total}\left({}^{90} Y\right)}=\mathrm{V}\mathrm{O}{\mathrm{I}}_{\mathrm{counts}}:\mathrm{tota}{\mathrm{l}}_{\mathrm{counts}} $$
$$ D\left[\mathrm{Gy}\right]=50\cdot \frac{A_{\mathrm{VOI}}\left[{}^{90} Y\right]}{M_{\mathrm{VOI}}\left[\mathrm{kg}\right]} $$

A more sophisticated evaluation can be made by the voxel dosimetry approach or by Monte Carlo modeling that provides information on dose distribution and expected radiobiologic effects at the voxel level [102].

Producers indicate different approaches to choose the amount of activity to be injected for the two radiopharmaceuticals [101]. Three main methods are suggested [101] for resin spheres: the empirical method, the body surface area (BSA)-based method, and the partition method.

The empirical method does not personalize the treatment for different liver dimensions or tumor avidity, but it takes into account the tumor involvement and attempts to lower the radiation risks to the lungs and the NT tissues. With this, method activities range from 1.2 to 3.0 GBq, and the doses received by the lungs and by the NT are within 18 and 83 Gy, at most. According to Kennedy et al. [100]. “The Radio Induced Liver Disease (RILD) was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method.”

The BSA method, probably the most widely employed for resin microspheres, has been proposed since in normal patients, liver mass correlates with BSA. The basic equation, empirical, includes the patient body surface area: \( \left[\mathrm{BSA}\left({\mathrm{m}}^2\right)=0.20247\times \mathrm{H}0.725\times \mathrm{W}0.425,\mathrm{with}\;\mathrm{H}=\mathrm{height}\left(\mathrm{m}\right)\mathrm{and}\kern0.2em \mathrm{W}=\mathrm{weight}\left(\mathrm{kg}\right)\right] \) and provides a maximum activity supposed to be safe for NT and lungs, once applying the same restrictions for lung shunt as above:
$$ A=\left(\mathrm{BSA}-0.2\right)+\frac{M_{\mathrm{T}}}{M_{\mathrm{T}}+{M}_{\mathrm{L}}} $$
where A = activity (GBq), MT = tumor mass, and ML (g) = total liver mass. In general, the activities calculated by the BSA method are more conservative than those derived from the empiric method, never exceeding 2.5 GBq. Although including some individual parameters, the reliability of this method in terms of tailored evaluation should not be overemphasized. In fact, direct measurements in patients have provided evidence that the BSA-based estimates do not correlate with liver mass nor with tumor involvement. Comparison between the BSA-based and the dosimetry methods showed discrepancies in activities to be administered ranging from −30% to 35% [103].
In the partition method [104], the activity to be administered is calculated within the MIRD equations, once a limit dose is prescribed for NT; lung safety is also considered. Liver involvement, tumor avidity as compared to the NTL, and the possible occurrence of lung shunt are taken into account by the following equation:
$$ A={D}_{\mathrm{nL}}=\frac{A_{\mathrm{T}}\times {M}_{\mathrm{nL}}+{A}_{\mathrm{L}}\times {M}_{\mathrm{nL}}}{49,670\times {A}_L\left(1-\mathrm{LSF}\right)} $$
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 designed for single or discrete nodules, appropriate modification by a weighted T/NT ratio makes it easily applicable also to multiple lesions [105]. The review paper by Cremonesi et al. [101] provides the absorbed dose limits applied by several authors, including the most common recommendations [106] and more conservative approaches [105].

The model proposed for RE with glass spheres relies on a simplified dosimetry equation, in which the dose averaged on the injected liver (DL) is prescribed:
$$ A={D}_{\mathrm{L}}\times \frac{V_{\mathrm{L}}\times 1.03}{50\left(1-\mathrm{LSF}\right)} $$
where A = activity, DL(Gy) = prescribed liver dose, VL = total liver volume, and LSF = lung shunt fraction.

Absorbed doses to tumor and NT are not separately calculated, so no distinction is made for different tumor involvement or uptake ratios. Several studies [106] have indicated prescribed radiation doses (DL) of at least 100 Gy for a maximal effect on tumors, based on the fact that no dose-limiting organ toxicity has been observed in patients who had received nominal absorbed doses of up to 150 Gy. Mean cumulative doses to the treated liver as high as 200 Gy or even 390 Gy have been described as tolerated in patients affected by HCC with Okuda stage II and stage I who received multiple treatments [107]. Overall, these doses are apparently quite far from the limits recommended in the 90Y-resin approaches and much farther than the tolerance doses set by external beam radiotherapy (30–35 Gy) to avoid excessive risk of radiation hepatitis [105]. This is explained with the nonuniformity of absorbed dose deposition at the microscopic level, which is markedly higher for the less numerous glass microspheres [108]. Another basic point is the usually different administration technique. From the US experience following the split registration, glass spheres against HCC have been injected lobarly, while resin spheres against metastases were administered in the common hepatic artery. These are two completely different situations, since the lobar approach exploits the organ reserve and the regeneration capability of the liver [109].

The possibility of performing a real treatment planning in radioembolization is emphasized by the result of three studies, which applied radiobiological models to analyze response and toxicity after standard administration of microspheres. Strigari et al. [110] derived the normal tissue complication probability (NTCP) and tumor control probability (TCP) for HCC treated with resin spheres using post-therapy bremsstrahlung SPECT. TCP (50%) was at 150 Gy, while a dose above 200 Gy demonstrated response in all cases. Liver toxicity higher than G2 had a NTCP (50%) value of 52 Gy. Flamen et al. [111] found a good technetium MAA dose – FDG response correlation in colorectal metastases treated with resin spheres. Chiesa et al. [112] determined retrospectively with 99mTc-MAA SPECT the NTCP curve for Child A patients treated lobarly with glass microspheres, with a risk of radioinduced liver decompensation at 70 Gy if averaged over the whole non-tumoral parenchyma, including the non-injected lobe. This mean inclusive on the nontreated tissue is the simplest way to include the well-known liver volume effect (the smaller the irradiated fraction, the higher the tolerance). TCP was dramatically dependent upon the lesion size, being TCP (50%) = 250 Gy for masses less than 10 g and around 1,300 Gy for larger tumors. Garin et al. [113] were able to demonstrate a correlation between lesion absorbed dose and overall survival in HCC patient treated with glass spheres, with a cutoff of 205 Gy. Compared to Chiesa et al.’s results, this means that glass spheres require at least 205 Gy to stabilize the disease, while objective response requires higher dose. Individualized dosimetry-based administrations with increase of administered activity with respect to the producer indication were also safe and successful [114]. The unexplored way toward treatment planning in radionuclide treatment is open, thanks to dosimetry in radioembolization, which is the less demanding and that with higher impact among all kinds of radiopharmaceutical type of dosimetry. As a confirmation, for the first time in the history of nuclear medicine therapy, both 90Y-microsphere producers made investment in multicenter research about dosimetry [62].

Therapy of Neuroendocrine Malignancy

In the late 1980s, 131I-meta-iodobenzylguanidine (131I-MIBG) was used as a radiotherapeutic metabolic agent in neuroectodermal tumors, i.e., those tumors derived from the primitive neural crest (which develops to form the sympathetic nervous system). Malignant neuroectodermal tumors include pheochromocytoma, paraganglioma, carcinoid tumors, medullary thyroid cancer, and neuroblastoma.

As an analog of noradrenaline, at low concentrations 131I-MIBG is taken up into cells of neuroectodermal origin by the noradrenaline transporter (NAT). Once internalized, it is stored in intracellular storage granules. Transfer of MIBG from the cytoplasm into neurosecretory granules is mediated by an ATPase-dependent proton pump, and MIBG is not metabolized but excreted unchanged [115].

Treatment with 131I-MIBG is indicated for tumors showing adequate uptake and retention of radiolabeled MIBG on the basis of a pre-therapy diagnostic scan, which is performed using 123I-MIBG in children and either 123I-MIBG or 131I-MIBG in adults [116].

Most treatments regard neuroblastoma, the most common extracranial solid tumor affecting children (approximately 1 per 10,000 live births), most of the cases being diagnosed before the age of 4. Most of these malignancies originate in the nervous system, although about two-thirds of the cases arise in the abdomen near the adrenal glands. Distant metastases at diagnosis are frequent, and treatment of high-risk neuroblastoma includes surgery, chemotherapy, and 131I-MIBG [117].

In high-stage neuroblastoma, treatment with 131I-MIBG may be either palliative therapy, first-line therapy as a single agent or combined with chemotherapy, or consolidation therapy after induction of partial remission. More recently, this treatment has been used as second-line therapy after failed induction chemotherapy, combined with topotecan and stem cell rescue in children with metastatic neuroblastoma or with myeloablative chemotherapy and autologous stem cell transplantation in refractory neuroblastoma [118].

In addition to uptake in the tumor, 131I-MIBG accumulates in the liver, heart, lungs, and adrenal glands, while the bladder is irradiated by the urine-excreted metabolites of 131I-MIBG. Thyroid uptake of free radioiodide is prevented using oral stable iodine. Since many drugs can interfere with MIBG uptake and storage, these drugs should be withdrawn for adequate periods before treatment, and patients should be stabilized on alternative medication.

High-specific activity (up to 1.48 GBq/mg) is recommended for therapy, and single-administered activities range between 3.7 and 11.2 GBq, according to tumor burden or local legislation. Since several cycles of therapy with 131I-MIBG may be required to achieve objective response, these treatments are often repeated at widely different intervals, depending on blood count recovery; treatment is continued until the maximum clinical response is achieved.

Red bone marrow is the dose-limiting organ for 131I-MIBG therapy, and activity reduction should be considered in patients with myelosuppression or with impaired renal function. In patients with neuroblastoma who had received prior intensive chemotherapy, the dose-limiting toxicity of 131I-MIBG therapy is myelotoxicity at 2-Gy whole-body dose, according to the pre-therapeutic 131I-MIBG scans. This threshold can be circumvented if bone marrow stem cell support is available. A total of 4.0-Gy whole-body dose with stem cell rescue has been given with good tolerance and no other short-term, dose-limiting organ toxicity [119].

The approach to administer fixed activity “fractions” of 3.7–11.1 GBq offers the advantages of simplicity and shorter isolation and hospitalization period required for radioprotection; this feature in non-negligible when treating very sick children with poor prognosis.

Administration of high activities of 131I-MIBG based on body weight (555–777 MBq/kg), with stem cell support if necessary, has also been reported. A maximum tolerated activity of 444 MBq/kg is reported, combined with myeloablative chemotherapy and autologous stem cell transplantation [120].

However, when using fixed activities, no dose–response assessment or optimization on the basis of absorbed radiation dose is possible. Furthermore, the relatively LDR of radiation compared with (ultra)high doses may be viewed as radiobiologically suboptimal.

The results obtained over more than two decades demonstrate that whole-body absorbed doses correlate both with administered 131I-MIBG activity and with the subsequent development of hematological toxicity [121, 122].

An administered activity of 444–666 MBq/kg of 131I-MIBG may deliver 50–700 cGy of whole-body absorbed dose; 80% of patients with advanced chemorefractory stage III/IV neuroblastoma can develop grade 3 or 4 hematotoxicity at a whole-body absorbed dose of 2.5 Gy established from a pre-therapy 131I-MIBG scan.

In relapsed or refractory neuroblastoma, the whole-body absorbed dose calculated according to the standard MIRD schema can be prescribed accurately and allows higher activities of 131I-MIBG to be administered within the safety limits for bone marrow toxicity [123].

The mean absorbed dose, D, is given by the product of the cumulated activity and the MIRD whole-body-to-whole-body S value, that is [124]:
$$ {\overline{D}}_{\left(\mathrm{WB}\leftarrow \mathrm{WB}\right)}=\overrightarrow{A}\times {S}_{\left(\mathrm{WB}\leftarrow \mathrm{WB}\right)} $$
Value S(WB ← WB) is often obtained using the following equation (correction for body weight):
$$ {S}_{\left(\mathrm{WB}\leftarrow \mathrm{WB}\right)}=1.34\times {10}^{-4}{m}_{\mathrm{p}}^{-0.921} $$
where mP is the patient’s mass in kilograms. This equation was generated by interpolating the S(WB ← WB)values from the MIRD phantoms for a newborn as well as for 1-year, 5-year, 10-year, and 15-year-old children, and finally for an adult, each of which has a specific mass. Table 5 reports the absorbed doses to the organs calculated for unit of 131I-MIBG activity administered.
Table 5

Median and range organs absorbed doses values (Gy) for 131I-MIBG, per unit of activity administered (MBq/kg)


Fielding [74]

Matthay [79]

Gaze [81]

Koral [82]

DuBois [78]

131I-MIBG activities (MBq/kg, range)


555 (93–770)


572 (431–683)

666 (599–770)


Absorbed doses (Gy, range)

Whole body

1.9 (0.7–2.6)

2.28 (0.57–6.50)

2.19 (1.7–2.9)


2.92 (1.73–4.18)

Red marrow

2.0 (0.9–2.6)

2.20 (0.44–3.29)


3.47 (2.06–5.02)


0.8 (0.2–1.9)

1.77 (0.79–3.53)



5.3 (1.6–11.3)


13.1 (7–19)


An experimental MIBG protocol has been proposed in which the aim was to deliver a total whole-body absorbed dose of 4.0 Gy in two fractions, in combination with topotecan, after failure of induction chemotherapy [125]. Post-therapy dosimetry is performed after a first fixed fraction of 444 MBq/kg, with calculation of the activity dose to be administered with the subsequent second fraction in order to achieve the desired total whole-body absorbed dose of 4 Gy [126].

Recent studies analyzed the whole-body radiation dose (WBD) and tumor-absorbed doses from 131I-MIBG therapy in relation to tumor response and toxicities. Trieu et al. [127] retrospectively evaluated a cohort including 213 patients with high-risk neuroblastoma treated with 131I-MIBG between 1996 and 2015 to correlate WBD from 131I-MIBG with tumor response, toxicities, and other clinical factors. The WBD was calculated for every patient using radiation exposure rate measurements obtained by a ceiling-mounted ionization chamber or by a handheld ionization chamber. They found that WBD correlated with 131I-MIBG activity, particularly with 131I-MIBG administered per kilogram suggesting that activity prescriptions for 131I-MIBG therapies should be made based on patient weight as opposed to a predetermined total activity dose in order to achieve a targeted WBD. A recent study by Minguez et al. proposed an equation, which describes whole-body absorbed dose per unit of administered activity as a function of patient mass, as an alternative for prescriptions of activity on first administration when dosimetry data for the individual patient are unknown [128]. However, Trieu et al. [127] found no relationship between WBD and overall response, and they were unable to establish any relationship between hematologic or thyroid toxicity and WBD. This unexpected finding prompts future studies to evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with 131I-MIBG.

A study like this has been made by George et al. [129] who evaluated the response, toxicity, and long-term outcome of 131I-MIBG therapy in the treatment of refractory or relapsed neuroblastoma following a dosimetry-based 3D individualized approach performed in 8 of the 25 patients.

To calculate tumor-absorbed doses, image data were obtained by 38 SPECT acquisitions performed on consecutive days following the treatment. Reconstructed SPECT scans for each patient were sequentially coregistered to allow 3D voxelized dosimetry to be performed using an in-house dosimetry software package (Qrius). The image-based 3D dosimetry application provided an absorbed dose map of consecutive therapies from which dose–volume histograms (DVH) were derived.

To date, there is no clearly defined methodology to incorporate DVHs in patient-specific planning or to compare DVHs for individual therapies or to relate to outcome. However, it is clear that dose heterogeneity could affect the outcome of subsequent therapies and may partially explain the variation in responses. In light of this, a 3D dosimetry approach where DVHs are taken together with tumor-absorbed dose as well as dose-limiting criteria provides a reasonable method to help plan patient-specific treatment and should be used as a guideline to inform subsequent therapies.

A dosimetry-based approach on the basis of patient pharmacokinetics may often result in the administration of higher activities with excellent response rates while keeping toxicity within acceptable limits. However, to date, there are currently no published randomized controlled trials of 131I-MIBG therapy for neuroblastoma at any stage of treatment [21]. To maximize the therapeutic potential of 131I-MIBG therapy and to determine its place within the patient pathway, well-designed clinical trials incorporating dosimetry are needed.

Future studies, including more accurate tumor dosimetry such as 124I-MIBG with PET/CT technology, could improve the assessment of the relationship between WBD, tumor-absorbed doses, and overall response [130, 131]. Seo et al. [130] estimated expected radiation dose in tumors from 131I-MIBG therapy using 124I-MIBG micro-PET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter. The three-dimensional tool used for estimating the radiation dose that evaluated a range of activity of 52.8–206 MBq could deliver about 20 Gy to tumors.

Patient-specific dosimetry, using quantitative 124I-MIBG PET/CT with a GEometry ANd Tracking 4 (Geant4)-based Monte Carlo method, was used by Huang et al. [131] in a 10-year-old girl with relapsed neuroblastoma. Organ-absorbed dose for the salivary glands was 98.0 Gy, heart wall 36.5 Gy, and liver 34.3 Gy, while tumor-absorbed dose ranged from 143.9 to 1,641.3 Gy in different sites.

Finally, the use of 124I-MIBG PET/magnetic resonance imaging (MRI), performed with an integrated PET/MRI system, could be a promising technique in dosimetry as it improves tumor delineation because of the high soft tissue contrast in MRI. In a case reported by Hartung-Knemeyer et al. [132], PET/MRI allowed a more accurate volumetry in comparison to PET/CT, resulting in a reduction of the calculated lesion dose in abdominal muscle lesions up to 70%.

Treatment of Metastatic Bone Pain

Bone pain due to osseous metastases constitutes the most frequent type of pain among all cancer patients, with different prevalence among the various types of cancers. In general, oncological practice, breast and prostate cancers are responsible for more than 80% of the cases with bone metastases [133].

The pathophysiology is not well understood, and multiple mechanisms are postulated, including tumor-induced cytokines, stimulating factors released by tumor cells, direct nerve injury, and infiltration of the bone trabeculae and matrix by tumor cells causing osteolysis [134]. The appropriate management of painful skeletal metastasis includes the use of systemic analgesics, hormones, chemotherapeutic agents, steroids, external beam radiation therapy (EBRT), radiofrequency ablation, local surgery, and radiopharmaceuticals.

Curative options for multiple skeletal metastases unfortunately, do not exist, and most of the described treatments are palliative [133]. Systemic RNT has shown its value in the management of painful bone metastasis in clinical practice, although it remains an infrequently used treatment modality for many physicians, even those working in the fields of oncology and nuclear medicine [133, 135].

Phosphorus-32 (32P-ortophosphate) and strontium-89 (89Sr-chloride) were the first bone-seeking radiopharmaceuticals approved for the treatment of painful bone metastases [136], while bisphosphonates labeled with either 153Sm [137], 186Re [138], or 188Re [139] are newer among the traditional bone-seeking radionuclides [140].

Although there are some differences in the physical half-life, beta energy, penetration range, and biochemical characteristics among the various bone-seeking radiopharmaceuticals, no clear advantage in terms of increased response rate has emerged. A uniform response rate of approximately 70% has been reported with all bone-seeking radiopharmaceuticals, and the response appears to be inversely proportional to disease extent and Karnofsky index [133, 135].

Several detailed dosimetric studies have been reported for bone-seeking radioisotopes. All the radiopharmaceuticals have shown an approximate tenfold therapeutic ratio between the metastasis and bone, although there is an order of magnitude difference 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].
Table 6

Radiation dosimetry of radiopharmaceuticals used for treatment of refractory metastatic bone pain


89Sr-chloride (mGy/MBq)

153Sm-EDTMP (mGy/MBq)

186Re-HEDP (mGy/MBq)

Bone surface




Bone marrow




Lower bowel wall




Bladder wall
















From Bodei et al. [141], with permission

Hematological toxicity is the dose-limiting factor, usually presenting as thrombocytopenia. Although there is a clear relationship between metastatic burden and toxicity, the correlation between thrombocytopenia and absorbed dose calculations is difficult to be noticed [133] even though there have been some exceptions [142].

The bone-seeking agent of choice has not yet been determined. Since all the commonly used radiopharmaceuticals have similar efficacy profiles, the agent should be selected in a case-based fashion taking into consideration the availability, toxicity, and goal of therapy.

It is intriguing that all studies that have searched for a dose–response relationship have failed to show a correlation between absorbed dose to metastasis and clinical response. Some of these calculations have shown clinical responses at absorbed doses for which classical radiobiological paradigms would predict no likelihood of response. Furthermore, no correlations have been found with primary endpoints, such as overall survival.

Recently, many clinical trials have shown the safety and efficacy of the 223Ra-dichloride for patients affected by metastatic castration-resistant (hormone-refractory) prostate cancer (CRPC), leading to approve the 223Ra-based drug (Xofigo©) for the treatment of adults with CRPC, symptomatic bone metastases, and no known visceral metastases. For the first time, therapy with a bone-seeking agent showed a life expectancy longer than that of patients in the placebo group, delaying the start of bone fractures and pain [143]. 223Ra is a calcium mimetic (half-life 11.4 days) alpha emitter. The high linear energy transfer (LET) of alpha radiation gives rise to a greater biological effectiveness than beta radiation and to cytotoxicity that is independent of dose rate, cell cycle growth phase, and oxygen concentration [144]. The range of alpha particles (<100 μm) is much shorter than that of beta radiation, causing less hematological toxicity for a given absorbed dose to the bone surface than beta emitters [145]. Actually, several trials are ongoing for dose escalation and combination therapy (e.g., with hormone therapy). 223Ra emits also a small number of photons useful for imaging, so in vivo image-based dosimetry is feasible (even though challenging), allowing investigations on a macrodosimetric scale [146, 147, 148], as well as the traditional microdosimetric approach to study the mechanisms of action of the alpha radiation [144].

Biological Dosimetry

Study of the biological effect induced by ionizing radiation on living organisms has systematically relied on the analysis of cytogenetic indicators, requiring the definition of several theoretical approaches to be interpreted [149]. Biological dosimetry, based on the investigation of biophysical and biological endpoints to estimate absorbed dose, is usually employed in cases of actual or suspected radiation overexposure. Although several biological samples can be considered representative of individual exposure, dose assessment is usually performed on peripheral lymphocytes. This cell population represents a suitable biological model to investigate radiation-induced effects, since it circulates in the body and remains quiescent in the G0 stage of the cell cycle for a relatively long time.

Chromosomal aberrations induced by ionizing radiation can be classified as stable or unstable abnormalities. Stable anomalies, being consistent with cell survival, can persist for many years and involve reciprocal, nonreciprocal, and interstitial translocations. Unstable anomalies, inducing mitotic cell death, decrease with time and include dicentrics, centric rings, and acentric aberrations. Chromosomal aberrations scored in lymphocytes represent a suitable long-term biomarker of whole-body exposure and provide a fairly accurate index of bone marrow dose [149]. The estimate of individual exposure is obtained comparing the dose–effect relationships of aberrations measured by scoring with the dose–response relationships observed in in vitro models.

Biological dosimetry may be particularly useful in the assessment of individual response to radiation, providing an important contribution to the development of personalized therapy planning and radiation protection, as well as to establish radiation-induced risk and drugs effects, meant to decrease the radiation-induced side effects.

Although the efficacy of biological dosimetry is established in many cases, the method has some limitations. Accurate dose assessment in case of RNT can be very complex, because of the inhomogeneities in body irradiation and the LDR of irradiation. Correction for inhomogeneous irradiations can be performed, employing contaminated Poisson distribution method. The distribution of observed aberrations among cells is compared with that expected from a normal Poisson distribution. Nevertheless, a large number of aberrations, not always achievable, are required [150]. In case of LDR of exposure, the comparison with in vitro exposure can be hazardous. Indeed, repair can occur during exposure, reducing the quadratic component with dose rate decreasing as exposure is spread over a longer period of time [150]. No valid solution for this problem has yet been developed.

Furthermore, biological dosimetry assessment is complex when long retrospective dosimetry is needed, because of disappearance of lymphocytes carrying unstable aberrations [150]. Several years after exposure, scoring of stable aberrations might appear more appropriate, although involving more laborious and expensive techniques (G-banding, FISH). The sensitivity of biological dosimetry is reduced when doses are very low (e.g., below 0.1–0.2 Gy), because of the relevant contribution from environmental factors (light, chemicals, oxidative species originated by metabolism, smoking, and aging) to DNA damage. Moreover, individual variability in repair of radiation damage can affect dosimetry outcome. Finally, the biological effects on circulating lymphocytes due to exposure of low radiation doses are sparse and difficult to measure, so cumulative radiation exposure can be slightly underestimated.

Assays in Biological Dosimetry


One of the most commonly used biology dosimetry assay is the count of dicentric chromosomes, selected as suitable biomarkers because of their rare spontaneous occurrence and their specificity for ionizing radiation [149].

Despite the high specificity observed for acute exposure radiation damage, the method appears cumbersome and unsuitable for dose assessment with prolonged delayed blood sampling. Even if lymphocytes with aberrations continue to circulate in peripheral blood for many years after irradiation, a delay longer than 6 weeks between irradiation and sampling can cause reduction in aberration yield, with a consequent dose underestimation.

Chronic exposures may not be easily determined by dicentric aberration scoring. It would be reasonable to postulate that repair must play a significant role in the effects of LDR. A study by M’Kacher et al. [151] described the use of biological dosimetry in patients receiving repeated treatments with 131I-iodide for differentiated thyroid cancer (DTC), resulting in cumulative doses from 1.0 to 3.5 Gy. A reliable retrospective dosimetry based on chromosomal aberration analysis (number of dicentric and chromosome 4 painting) was achieved only for samples collected following the first two treatment cycles but not from the third treatment and onward. At this stage, estimated doses were considerably lower than those delivered, suggesting that apoptosis occurring in lymphocytes with multiple chromosomal anomalies could affect the dosimetry outcome following repeated irradiations [151].


Micronuclei (MN) can be the result of small acentric chromosome fragments that are not incorporated into the daughter nuclei during cell division. They are enveloped by a nuclear membrane and appear as small nuclei – micronuclei – in the cytoplasm outside the main daughter nuclei. They arise during exposure to various clastogenic agents and are the result of non- or misrepaired DNA double-strand breaks. Because of its high reliability and reproducibility, the MN assay has become one of the standard cytogenetic techniques for genetic toxicology testing in human and for mammalian cells in general [149].

The baseline, spontaneous frequency of MN is quite variable and can be affected by factors related to diet, age, and gender. Such variability clearly poses limitations on using MN as a biological dosimeter, particularly for low doses where preexisting individual background frequencies are not known.

The MN assay in peripheral blood lymphocytes is an appropriate biological dosimetry tool to evaluate in vivo radiation exposure and to assess in vitro radiosensitivity and radiation risk. Many studies showed that the number of radiation-induced MN is strongly correlated with radiation dose and radiation quality, but sensitivity of the assay is limited to 0.2 Gy. This is due to the relatively high and variable spontaneous MN yield that is an inherent limitation of the assay for low-dose estimation. The spontaneous MN yield increases systematically with age, and MN disappearance is very similar to that observed for dicentrics. This result is in agreement with the decline in the MN frequency following irradiation (around 60%, 1-year posttreatment), observed in patients undergoing radiotherapy.

In a study by Monsieurs et al. [152], the MN assay was used to estimate the radiation-associated risk in patients receiving 131I-iodide treatment for hyperthyroidism and thyroid remnant ablation after surgery for thyroid carcinoma. Surprisingly, the number of micronuclei induced by the different procedures, although the activity of 131I-iodide was much higher in the thyroid cancer group, was similar. When this was compared to MN induction by EBRT in patients with cervical carcinoma or with Hodgkin’s lymphoma, it was seen that EBRT was associated with a much higher degree of radiation toxicity. The author concluded that this might have been a suitable explanation of the different rates of induction of secondary cancer observed in the two therapeutic approaches.

A recent study employed the MN assay to evaluate the radioprotective effect of ginkgo biloba extract (GBE). It was demonstrated that the use of GME significantly reduced the number of MN after 131I ablation therapy in thyroid cancer patients [153].

Chromosome Painting

Fluorescence in situ hybridization (FISH) allows a rapid and accurate characterization of chromosome or chromatid region by using specific DNA sequences labeled with fluorescent molecular probes. FISH painting is a single rapid method, allowing simultaneous evaluation of many types of aberration (dicentrics and single or complex translocations) [149]. Accuracy in translocation detection can be improved by using multiple color painting. Although dicentrics are less stable than translocations, they have background frequencies that are lower in unexposed people. This makes it easier to detect the effects of lower exposure doses, provided that exposure was recent and acute. In contrast, the relative stability of translocations makes them more suitable for analysis of chronic or temporally displaced exposures. Although translocation frequencies were initially thought by some investigators to be fully persistent, many studies have observed their decline with time following exposure, in some cases reaching a dose-related plateau [153].

Comet Assay

The comet assay (single-cell gel electrophoresis) is a fast, sensitive, and not expensive technique to measure DNA damage in a single cell [154]. At variance with the cytogenic assays previously described, the comet assay can be performed in any phase of the cell cycle, cells do not need to be cultured, and sterile conditions are not required. It can be applied to all cell types, only a few hundreds are needed, and by this technique it is possible to measure single- or double-strand DNA breaks and the apoptotic index.

In the comet assay, cells are mixed with agarose and layered on microscope slides, where they are lysed and subjected to electrophoresis; staining with fluorescent dyes such as DAPI or ethidium bromide permits microscopic visualization of the “comets.” DNA containing breaks unwinds and migrates away from the “head” (the nucleus), forming a “tail”; quantification of the amount of DNA in tails and in heads of comets provides an estimate of the frequency of strand breaks. Chromosomal aberrations measured by comet assay do not last long, since they can either be repaired or lead to cell death [155].

Gutierrez et al. [156] used the comet assay to measure the radiation damage in patients treated with 131I-iodide for hyperthyroidism, reporting only a slight increase in DNA breaks 1 month after treatment. These results, however, were less clear to interpret compared to the MN assay, owing to the high sensitivity of the test, but the poor specificity that may affect the results especially in longitudinal studies.


The nucleosomal core histone variant γ-H2AX forms part of the cellular DNA damage response. Exposure to ionizing radiation triggers the large-scale activation of specific DNA damage signaling and repair mechanisms. This includes the phosphorylation of H2AX in the vicinity of a DSB. Foci of phospho-H2AX (γ-H2AX) form over large chromatin domains surrounding DSBs. The formation and loss of γ-H2AX foci have been measured following exposure to radiation doses as low as 1 mGy, and foci yields have been shown to increase linearly with dose [157]. Moreover, the initial number of γ-H2AX foci formed per cell nucleus following ionizing irradiation agrees with the yield of induced DSBs. Foci disappearance over time follows DSB rejoining in repair-competent cells; there is a close one-to-one relationship between initial and residual radiation-induced DSBs and γ-H2AX foci. These include rapid and potentially automatable processing and analysis, sensitivity to doses of a few milligrays, linear dose response across a broad dose range, ability to use unstimulated lymphocytes obtained by minimally invasive procedures, and potential to reveal partial body exposures. A recent article described the use of γ-H2AX in thyroid cancer patients undergoing thyroid remnant ablation therapy. The technique was used to assess double-strand breaks starting 0.5–120 h after treatment, and it was possible to demonstrate the early start of DNA damage by a linear dose-dependent increase and a bi-exponential response function describing a fast and a slow repair component [158].

However, severe limitations associated mainly with the rapid loss of the γ-H2AX signal following irradiation have to be considered. They are likely to restrict the use of the γ-H2AX to very recent radiation exposures – less than 2 days before blood sampling. Since the yield of γ-H2AX per unit dose changes rapidly over time, dose–effect curves for calibration of the assay are required for multiple time points.


Although dosimetry has been of great value in the preclinical phase of radiopharmaceutical development, its clinical use to optimize administered activity on an individual patient basis has been less evident. Similarly, little attention has been paid to radiobiology in therapeutic nuclear medicine, which exhibits significant differences with respect to the biologic effects of EBRT. However, data in the literature which underscore the potential of dosimetry to avoid under- and overdosing and the importance of radiobiology in RNT are increasing.

The recent proliferation of PET/CT and SPECT/CT cameras, the development of patient-specific 3D imaging-based dosimetry, and the availability of faster computers and improved Monte Carlo methods will offer more and more major scientific and clinical opportunities in RNT dosimetry improving the physics of absorbed dose estimation. Furthermore, the increasing scientific interest in the radiobiological features specific to radionuclides will improve our knowledge in nuclear medicine therapy and will advance our ability to administer this treatment modality optimally.

As stated by Edith Quimby in 1969 “Radionuclide dosimetry is not a finished product, but it has come a long way from the early empiric days. We must be grateful to the patient people who have spent untold hours on these developments” [158].


By incorporating adequately large activities of appropriate radionuclides into target tissue-avid radiopharmaceuticals, a sufficiently high radiation dose can be delivered to produce a therapeutic response in tumors or other tissues. However, such high administered activities can also ensue some radiation injury in normal tissues. Nevertheless, nuclear medicine remains largely a diagnostic specialty, where relatively low administered activities are administered to yield important clinical information whose benefit far outweighs the small potential risk associated with the attendant low normal tissue radiation doses. The radiation doses associated with diagnostic administration of radiopharmaceuticals are typically of the order of 1 cSv [159], well below the threshold doses associated with the deterministic effects of radiation described in the prior section. Average normal tissue doses are received by the “standard” patient, found in package inserts for approved radiopharmaceuticals and in reports issued by authoritative bodies such as the International Commission on Radiological Units (ICRU), even though the actual doses received by a particular patient may deviate significantly from these average values. For such procedures, the radiation effects of practical concern are stochastic (or statistical) effects, i.e., possible germ-cell mutagenesis and, in particular, carcinogenesis.

Medical Radiation Exposures: Societal Concerns

The clinical applications of diagnostic nuclear medicine, particularly PET and nuclear cardiology, as well as computed tomography (CT), have grown dramatically over the last several decades. In the USA, for example, the annual number of nuclear medicine procedures has increased threefold (from 7 to 20 million) and the annual number of CT procedures 20-fold (from 3 to 60 million) between 1985 and 2005 [160], much of the increase in the latter being related to the use of CT in children (up to ∼ 10% of all such procedures). As a result of this increased medical exposure of the population, the average (i.e., per capita) annual background dose in the USA has nearly doubled, from 3.0 to 5.6 mSv [161]. There has been increasing concern in the medical profession and in the popular press over the potential public health impact – namely, an increased risk of cancer – associated with this dramatic growth in exposure from diagnostic radiology and nuclear medicine. Brenner and Hall, for example, have estimated that as much as 2% of all cancers in the USA may be attributable to CT irradiation [162]. While nuclear medicine diagnostic procedures are not performed as frequently as CT scans and the radiation doses are generally not as high, the radiogenic cancer risk per procedure is comparable. For all the diagnostic procedures, the relevant parameters should always be judiciously selected to deliver the minimum radiation dose consistent with yielding the clinical information being sought, according to a commonsense approach as emphasized in the “Image Gently” campaign [163, 164, 165, 166] promoted by many agencies and professional organizations.

Nuclear medicine practitioners must be prepared to rationally address the “cancer-risk” concerns of patients, referring physicians, regulators, and other stakeholders.

Radiation Doses in Diagnostic Nuclear Medicine


Table 7 is a compilation of radiation doses for common diagnostic nuclear medicine procedures in terms of the effective dose (ED) for the 70-kg standard adult anatomic model [159, 167, 168]. Effective dose is used in radiation protection to compare the stochastic risk of a nonuniform exposure to ionizing radiation with the risk associated with a uniform whole-body exposure. It is a weighted sum of the doses to the individual tissues/organs of the body, where the tissue weighting factor reflects the relative susceptibility of that tissue to stochastic damage (i.e., carcinogenesis or, in the case of germ cells, germ-cell mutagenesis). EDs for such procedures are usually of the order of 1 cSv for typical administered activities, meaning that the overall risk of carcinogenesis (and germ-cell mutagenesis) is roughly equivalent to that of a uniform whole-body dose of 1 cGy. Anatomic models and relevant dosimetric quantities such as absorbed fractions are now available [168], and radiopharmaceutical doses have thus been estimated for newborns, 1-year-olds, 5-year-olds, 10-year-olds, and 15-year-olds as well as adults [168, 169, 170]. There is typically a several-fold or greater difference in doses among organs for a particular radiopharmaceutical and anatomic model [171] for fluorine-18-labeled fluoro-deoxyglucose ([18F]FDG) in the Standard Adult anatomic model. Furthermore, as emphasized by several authors ­[172, 173, 174], one should use organ-, age-, and gender-specific doses and risk factors, rather than the ED and the overall risk factor, to estimate the cancer risk(s) associated with a particular procedure.
Table 7

Radiation doses for diagnostic nuclear medicine procedures for the 70-kg standard man anatomic model



Administered activity (MBq)

Effective dose cSv/MBq

cSv total
















Thyroid scan

123I Na




Thyroid scan





Parathyroid scan





Cardiac stress–rest test





Cardiac rest–stress test

99mTc-sestamibi 1-day protocol




Cardiac rest–stress test

99mTc-sestamibi 2-day protocol




Cardiac rest–stress test





Cardiac ventriculography

99mTc-labeled red blood cells









Lung perfusion





Lung ventilation





Lung ventilation






99mTc-sulfur colloid




Biliary tract





Gastrointestinal bleeding

99mTc-labeled red blood cells




Gastrointestinal emptying

99mTc-labeled solids







































White blood cells





White blood cells










From Mettler et al. [207], with permission

aDMSA dimercaptosuccinic acid, DTPA diethylenetriaminepentaacetic acid, ECD ethyl cysteinate dimmer, 18 F fluorine-18, FDG fluoro-deoxyglucose, HMPAO hexamethylpropylenamine oxine, 111 In indium-111, MAA macroaggregated albumin, MAG3 mercaptoacetyltriglycine, MDP methylene diphosphonate, 99m Tc technetium-99m, 201 Tl thallium-201

b15% thyroid uptake

c0.00079 cSv stress, 0.00090 cSv rest

d40 MBq actually inhaled

Multimodality Studies: PET/CT and SPECT/CT

As noted, there has been growing concern regarding the radiation dose associated with CT studies, particularly for the pediatric patient population [162, 172]. When CT is performed as part of a SPECT/CT or a PET/CT study, the axial field of view may be much larger than that of conventional CT studies, routinely extending from the base of the skull to the mid-thigh and thus potentially yielding an ED considerably greater than that of conventional, limited field-of-view CT studies [175]. Accordingly, when the CT component of a PET/CT study is used for attenuation correction and anatomic localization rather than for radiologic diagnosis, the CT scan parameters can, and should, be adjusted to appropriately reduce the CT dose. X-ray beams are characterized by (1) the current (expressed in units of milliampere (mA)) between the anode and cathode and (2) the maximum or peak (p) voltage (expressed in thousands of volts (V), or kilovolts (kV), and represented as “kVp”) between the filament and the metallic target, where the electrons accelerated across this potential difference are stopped and the bremsstrahlung X-rays produced. Helical, or spiral, CT scans are also characterized by the pitch, the distance of travel of the patient table per rotation of the X-ray tube, and detector assemblies. The X-ray intensity and therefore the radiation dose are proportional to the mA and approximately proportional to the square of the kVp value. The dose is inversely related to the pitch. To determine the minimum-dose CT acquisition parameters that are compatible with accurate attenuation correction, investigators have systematically evaluated the impact of such parameters and therefore patient dose on both CT 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]FDG standard uptake values (SUVs) and measured lesion sizes, with no significant difference in SUVs and lesion sizes between 68Ge- and CT (80 mA)-attenuation-corrected PET scans. The authors concluded that CT scans using tube currents as low as 10 mA yield adequate attenuation correction for PET. Fahey et al. [175] subsequently evaluated the dose from the CT component of PET/CT studies to determine minimum-dose CT acquisition 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 correction for a range of patient sizes (i.e., anatomic phantoms) from newborns to adults. The CT dose index (CTDI), a commonly used CT dosimetry parameter indicative of the ED, varied by two orders of magnitude for each phantom over the range of acquisition parameters (e.g., for the 10-year-old-sized phantom, the CTDIs were 0.030 and 2.1 cSv for 80 kVp, 10 mAs, and 0.8 s and for 140 kVp, 160 mAs, and 0.8 s, respectively). The CTDI for the newborn phantom was twice that for the adult phantom for the same CT acquisition parameters. The 68Ge rod source dose was only 0.003 cSv (3-min scan). Although CT statistical uncertainty (i.e., mottle or “noise”) varied substantially among acquisition parameters, its contribution to PET noise was minimal (<∼2%). In a pediatric phantom, PET images generated using CT performed with 80 kVp and 10 mA for attenuation correction were qualitatively and quantitatively indistinguishable from those generated using CT performed with 140 kVp and 160 mA. Importantly, however, with very low-dose CT (80 kVp, 10 mA) for the adult phantom (i.e., for the combination of both low kVp and low mA), systematic undercorrection of the PET data for attenuation resulted. The impact on dose of these different CT 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, 178, 179] and therefore a total ED of 3.3 rem. However, for attenuation correction of an [18]FDG PET scan in an adult, a quantitatively accurate but nondiagnostic CT scan (e.g., with a kVp of 120, mAs of 60, and pitch of 1.5) delivers an ED of only 0.60 cSv [175, 177, 178, 179] and therefore a total ED of 1.7 cSv. For smaller patients a tube current as low as 60 mA can be used (with a kVp of 120 and a pitch of 1.5); the CT ED is only 0.1 cSv [175, 177, 178, 179]. Thus, if the purpose of the CT component of a SPECT/CT or PET/CT study is attenuation correction and anatomic registration and not radiologic diagnosis, appropriately judicious selection of the CT parameters can reduce the total ED by over 50% without compromising the diagnostic information content and quantitative accuracy of the PET study.

Dose–Response Relationships in Radiation Carcinogenesis

The largest and best characterized human cohort exposed to significant amounts of ionizing radiation remains the A-bomb survivors in Hiroshima and Nagasaki. Not surprisingly, A-bomb dosimetry had long been uncertain and plagued by a number of unresolved issues, including the yield of the Hiroshima bomb, the dose contribution of activation products, and the RBE and magnitude of the neutron dose. The latest A-bomb dosimetry system, Dosimetry System 2002 (DS02), improves on the Dosimetry System 1986 (DS86) and earlier A-bomb dosimetry systems in many important details, including the specifics of the radiation released by the bombs, addition of significant numbers of survivors to the so-called Life Span Study (LSS), and the effects of shielding by structures and terrain, and has thus resolved many of the outstanding dosimetric issues [180].

Choice of the correct model (i.e., mathematical relationship) between the excess cancer risk and radiation dose for extrapolation of the A-bomb dose–response data from its historical “high-dose” (>100 cSv) range to the diagnostic or “low-dose” (<10 cSv) range has long been controversial. The basic choices for such a mathematical extrapolation model are the supralinear model, the sublinear (i.e., linear-quadratic) model, and the linear, no-threshold model (Fig. 4). A supralinear model implies that the cancer risk per cSv is actually higher at low doses than at high doses; there are no data or biophysical evidence to support such a model that has never been creditably considered. The sublinear (i.e., linear-quadratic) model has for many years been the generally accepted dose–response model. The available human data are generally consistent with such a model, as are certain biophysical models of radiation action at the molecular level. Importantly, the sublinear model implies that the risk per cSv is lower at lower doses than at the higher doses (at which data are actually available). With the publication of the BEIR V and BEIR VII Reports [181, 182], however, the linear, non-threshold model is now the prevailing model for solid tumors, while the linear-quadratic model is the model of choice for leukemias [181, 182]. The linear, non-threshold model implies that the risk per cSv is constant at all doses, and it further implies that any excess radiation dose (i.e., above background), no matter how small, carries with it a finite (i.e., nonzero) excess risk of cancer and genetic damage. The available A-bomb survivor data for solid tumors – now including significant numbers of survivors receiving doses as low as 5 cSv on the basis of DS02 [180, 183] – are consistent with the linear, non-threshold model as well as with the linear-quadratic model. That is, on the basis of statistical considerations such as goodness-of-fit, one cannot actually distinguish between the sublinear (i.e., linear-quadratic) and the linear, non-threshold models. The linear, non-threshold model is more conservative (i.e., predicts a higher risk per cSv at low doses) than the sublinear model and is therefore considered “safer” and thus more appropriate by some for radiation protection purposes. As noted, however, this issue remains controversial.
Fig. 4

Schematic representation of the basic choices for mathematical extrapolation of the A-bomb dose–response (i.e., excess cancer risk vs. radiation dose) data from its historical “high-dose” (>100 cSv) range to the diagnostic or “low-dose” (<10 cSv) range

The BEIR VII age at exposure- and gender-specific risk factors for solid tumor and leukemia incidence and mortality shows pronounced differences in radiogenic cancer risk (in terms of both incidence and mortality) depending on age at exposure and gender (especially at younger ages); there are large differences depending on the cancer site, with female breast, lung, colon, and urinary bladder being the most susceptible to radiation-induced cancer [182]. The risk factors incorporate a so-called dose-rate effective factor of 1.5, meaning that HDR (> ∼ 10 cSv/min or higher) radiation has a 50% higher risk factor than LDR (<∼1 cSv/min or lower) [182]. It is possible, however, that the dose-rate effectiveness factor may actually be higher than 1.5 and that the risk factors may therefore overestimate somewhat the cancer risk associated with the LDRs typical of diagnostic radiopharmaceuticals. Moreover, although stratified by age and gender, the risk factors within each stratum represent population-averaged values and thus do not account for individual differences in radiation sensitivity related to any preexisting condition, genetic susceptibility to radiogenic damage, etc. [174]. Importantly, as noted by Brenner and colleagues [162, 184], the risk factors they employed to estimate the numbers of radiogenic cancers associated with CT scanning are based on A-bomb incidence data at doses as low as 5 cSv – comparable to cumulative doses actually received by patients undergoing multiple CT procedures (as is often the case clinically) [4] – and not model-based extrapolation 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 with low (i.e., diagnostic)-level radiation – to the exclusion of any concrete consideration of its medical benefit. This is rather typical in the scientific literature: other than a perfunctory acknowledgment that the benefits of diagnostic procedures far outweigh any radiogenic risks, such benefits are rarely, if ever, quantitated in a manner comparable to that of quantitation of risk. An unintended consequence of such “unbalanced” analyses – that is, quantitation of risk without comparable consideration of benefit – may be the mistaken perception that the medical benefit of a diagnostic procedure does not far outweigh radiogenic risk. Alternatively, the lack of quantitation of benefit may result in procedures in which risk outweighs benefit unjustifiably persisting in clinical practice. As illustrated by the case study which follows, risk–benefit analyses should thus quantitatively incorporate both the medical benefit and the radiogenic risk of diagnostic procedures.

Van Tinteren et al. [185] compared the management and clinical of suspected non-small cell lung cancer (NSCLC) with and without preoperative [18F]FDG PET. With the conventional preoperative evaluation of NSCLC, that is, without [18F]FDG PET, 81% of patients underwent thoracotomy, and 41% of those thoracotomies were futile, that is, non-potentially curative, because of the progression of disease disclosed at surgery. In series of Van Tinteren et al. [185], the surgery-related mortality was 6.5%. Adding [18F]FDG PET to the preoperative evaluation reduced the proportion of NSCLC patients undergoing thoracotomy to 65%, with only 21% being futile. Thus, a non-curative operation was avoided in 20% of patients with the addition of [18F]FDG PET. If one extrapolates the foregoing data to the US population, with 174,470 new lungs per year, the conventional preoperative evaluation will result in \( 174,470\times 0.81\times 0.41\times 0.065=3,766 \) futile surgical deaths each year; the addition of [18F]FDG PET to the preoperative evaluation reduces the number of futile surgical deaths per year to \( 174,470\times 0.65\times 0.21\times 0.065=1,547 \) – a gross benefit of [18F]FDG PET 3,766 − 1,547 = 2,219 lives saved per year. However, for a 370-MBq administered activity of [18F]FDG, the ED is 1.4 cSv [159] and the number of radiogenic cancer-related deaths therefore \( 174,470\times 1.4\kern0.5em \mathrm{c}\mathrm{S}\mathrm{v}\times 0.0005/\mathrm{c}\mathrm{S}\mathrm{v}=122, \) where 0.0005/cSv is the mean cancer risk factor (i.e., the lifetime age- and gender-averaged fractional increase in excess cancer mortality) [182]. Thus, the addition of [18F]FDG PET to the preoperative evaluation of suspected lung cancer results in a net benefit of 2,219 − 122 = 2,097 lives saved per year. Such a balanced quantitative analysis thus provides some perspective for objective consideration of radiogenic risks and medical benefits.

Considerations for Sensitive Populations: Prospective Parents, Pregnant Women, and Nursing Mothers

Prospective Parents

Experimental studies in a number of nonhuman systems have established that gonadal irradiation at sufficiently high doses can result in demonstrable abnormalities in subsequently (i.e., postirradiation) conceived offspring of the irradiated parent(s). Importantly, however, despite comprehensive studies of well over 10,000 children born to the atomic bomb survivors in Hiroshima and Nagasaki receiving mean gonadal doses of over 30 cGy and individual gonadal doses of up to several hundred cGy, there remains no evidence for heritable radiation effects in man [182, 186]. Specifically, in children born to A-bomb survivors at least several years after the bombings, there was no statistically significant increase in any radiogenic heritable effect. This implies that for diagnostic nuclear medicine procedures, where the gonadal doses are of the order of only 1 cSv (an order of magnitude less the 30-cSv mean gonadal dose received by the A-bomb survivors), there is no significant risk of heritable adverse effects among the offspring of patients who undergo such procedures. The estimation of human genetic risks is thus based largely on data derived from laboratory studies in animals, introducing the considerable uncertainty of extrapolation from nonhuman systems to humans [187]. The estimated absolute and relative risk factors are approximately 50 additional genetic effects/million live 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 does not extend to therapeutic applications of radionuclides. Although a number of patients are small, demonstrable gonadal damage, such as reduced sperm counts and impaired fertility, may occur among 131I-iodide therapy patients over the first year posttreatment [182]. However, even among thyroid cancer patients treated with large (GBq) amounts of 131I-iodide and receiving gonadal doses of the order of 100 cSv, such damage is transient [188, 189]. For example, follow-up studies of such patients indicate that among male patients there is a time-dependent recovery of sperm count and serum follicle-stimulating hormone (FSH) to control levels by 2 years posttreatment [190]. Long-term studies (i.e., 10 years or longer posttreatment) among both male and female patients indicate that fertility and the frequencies of miscarriages and congenital abnormalities among their offspring are comparable to control values [190].

Pregnant Women

It is an established radiobiological principle that the conceptus is particularly sensitive to radiation effects. Radiation doses to the conceptus associated with diagnostic procedures – generally of the order of or less than 0.1 cSv per 37 mBq administered to the mother [191, 192, 193, 194, 195, 196, 197, 198] – are nonetheless well below the threshold doses for deterministic effects such as radiogenic fetal death or congenital malformations. Although modification of the standard anthropomorphic adult anatomic model [168] has yielded reasonably accurate dosimetric models of the conceptus–pregnant woman [191, 197, 198], radiopharmaceutical kinetic data in utero and therefore fetal dose estimates remain quite limited. For such procedures and at such in utero doses, the practical concern is the increased risk of childhood cancer. Published data, including the seminal Oxford Survey of Childhood Cancers [182, 199], indicate an excess risk of childhood cancer as high as 20% per Sv received in utero, with a linear response down to doses as low as 1 cSv. Signs alerting female patients and containing wording similar to, “If you are pregnant or if it is possible you may be pregnant, please notify the staff before the beginning of any procedure,” should therefore be prominently posted throughout a nuclear medicine department, particularly in waiting and/or dressing areas. Once informed that a female patient of childbearing age is pregnant or may be pregnant, the nuclear medicine physician should confer with the referring physician to arrive at a medically informed, documented decision that the planned procedure is or is not justified. In particular, because RNT typically involves the administration of high (typically GBq) activities, such therapy is generally contraindicated in pregnant women, unless there is no viable alternative. A serum pregnancy test should be performed before RNT in any female patient of childbearing age. Assertions by the patient and/or her family regarding the impossibility of a pregnancy because of medical condition, sexual inactivity, use of birth control measures, or recent menstrual history should not preclude performing a serum pregnancy test prior to RNT.

The use of 131I-iodide therapy for thyroid diseases in pregnant or potentially pregnant women is particularly problematic because radiogenic destruction of the iodine-avid fetal thyroid may result from such treatment and may result in hypothyroidism in utero with consequent cretinism [200]. The fetal thyroid begins concentrating iodine at the 12th–15th week of gestation, and fetal absorbed doses can be over 1,000 cSv per 3.7 GBq administered to the mother, depending on gestational age and maternal thyroid uptake. Therapeutic administered activities of 0.37–3.7 GBq of iodine would therefore result in fetal thyroid absorbed doses from 10,000 to 100,000 cSv, respectively. Case reports that include administered activity, gestational age, and follow-up of pregnant women treated with radioiodide for hyperthyroidism or thyroid cancer indicate that the outcome of pregnancy with regard to fetal thyroid function at birth did not appear to be compromised in the cases when radioiodide was given before the tenth week of pregnancy. However, there was essentially a 100% risk for congenital hypothyroidism and/or cretinism when radioiodine was administered thereafter, even in amounts less than 5 GBq [200]. Pregnancy is thus a contraindication to radioiodide therapy, and as stated above, a serum pregnancy test should be performed before administration of such therapy in any female patient of childbearing age.

Nursing Mothers

Virtually any systemically administered material, including a radiopharmaceutical, will appear to some extent in the breast milk of a lactating female, producing high activity concentrations in breast milk and potentially delivering significant radiation doses to nursing infants [201, 202, 203, 204, 205, 206]. In one study, for example, the cumulative breast milk activity ranged from 0.03% to 27% of 131I-iodide administered for thyroid uptake studies [206]. Because of an infant’s small size and the inverse relationship between absorbed dose and mass, ingestion of even a relatively small amount of activity will result in proportionately large total-body and organ absorbed doses. Furthermore, because of proximity of the infant to the mother when nursing, there is a potentially significant external absorbed dose to the infant. Signs alerting women with language such as, “If you are breast-feeding, please notify the staff before the beginning of any procedure,” should therefore be prominently posted throughout a nuclear medicine department. Using a variety of dosimetric criteria (e.g., an effective dose equivalent to the nursing infant of 0.1 cSv), a number of authors have recommended different interruption periods prior to resuming breast-feeding following administration of radiopharmaceuticals [201, 202, 203, 204, 205, 206]. The duration of the cessation of nursing will depend on the radionuclide and its effective half-life in vivo, the administered activity, and the extent to which radioactivity is concentrated in breast milk. While there is no absolute consensus, the following are representative of the published recommendations: 24 h following any administration of 99mTc, 2–4 weeks following administration of 67Ga-gallium citrate, and permanently for the current nursing infant following any administration of 131I-iodide, especially for administration of therapeutic amounts of 131I.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Massimo Salvatori
    • 1
    Email author
  • Marta Cremonesi
    • 2
  • Luca Indovina
    • 3
  • Marco Chianelli
    • 4
  • Massimiliano Pacilio
    • 5
  • Carlo Chiesa
    • 6
  • Pat Zanzonico
    • 7
  1. 1.Nuclear Medicine InstituteCatholic University of the Sacred Heart – Policlinico A. GemelliRomeItaly
  2. 2.Department of Medical PhysicsEuropean Institute of OncologyMilanItaly
  3. 3.Department of Medical Physics - Policlinico Universitario A. GemelliRomeItaly
  4. 4.Department of EndocrinologyOspedale Regina ApostolorumAlbano, RomeItaly
  5. 5.Department of Medical PhysicsAzienda Ospedaliera San Camillo ForlaniniRomeItaly
  6. 6.Nuclear Medicine DepartmentNational Cancer InstituteMilanItaly
  7. 7.Memorial Hospital Research Laboratories, Department of Medical PhysicsMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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