Description of the methodology for dosimetric quantification in treatments with 177Lu-DOTATATE | Revista Española de Medicina Nuclear e Imagen Molecular (English Edition)

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Selected axial fused PET/CT images: shoulder girdle, thorax, liver area. The whole-body MIP image shows irregular symmetric bilateral increase of 18F-FDG uptake on shoulder girdle muscle mass, as well as focal uptake on the subcutaneous cellular tissue in upper limbs and trunk, indicating inflammatory activity. On selected axial images, a hypermetabolic nodule on the upper inner quadrant of the left breast (SUVmax 6.5) is shown, together with ipsilateral axillary lymphadenopathy, also metabolically active (SUVmax 7.7). Hypoactive polycystic liver disease is also shown." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "S. Ortiz Banguera, J.R. Garcia Garzón, P. Bassa Massanas, M. Buxeda Figuerola, M.A. Kauak Kuschel, E. Riera Gil" "autores" => array:6 [ 0 => array:2 [ "nombre" => "S." "apellidos" => "Ortiz Banguera" ] 1 => array:2 [ "nombre" => "J.R." "apellidos" => "Garcia Garzón" ] 2 => array:2 [ "nombre" => "P." 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Monserrat Fuertes, F.M. González García, M.Á. Peinado Montes, M.L. Domínguez Grande, N. Martín Fernández, A. Gómez de Iturriaga Piña, P. Mínguez Gabiña" "autores" => array:7 [ 0 => array:4 [ "nombre" => "T." "apellidos" => "Monserrat Fuertes" "email" => array:1 [ 0 => "temonsfmpr@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "F.M." "apellidos" => "González García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "M.Á." "apellidos" => "Peinado Montes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "M.L." 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"apellidos" => "Mínguez Gabiña" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Servicio de Radiofísica y Protección Radiológica, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Cirugía, Radiología y Medicina Física, UPV/EHU, Leioa, Bizkaia, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Medicina Nuclear, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Oncología Radioterápica, Hospital Universitario Gurutzeta-Cruces/Instituto de Investigación Sanitaria BioCruces, Barakaldo, Bizkaia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Protección Radiológica y Radiofísica, Hospital Universitario Gurutzeta-Cruces/Instituto de Investigación Sanitaria BioCruces, Barakaldo, Bizkaia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Descripción de la metodología para la cuantificación dosimétrica en tratamientos con 177Lu-DOTATATE" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1223 "Ancho" => 1508 "Tamanyo" => 169111 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "The source regions are those which for physiological or pathological reasons accumulate activity of the radiopharmaceutical. The target regions are those for which the dose absorbed is of interest. The dose absorbed in a determined target region is due to the activity present in one or several source regions." ] ] ] "textoCompleto" => "IntroductionInternal dosimetry in radiometabolic therapy (RMT) is not a novel concept since the first basic dosimetric calculations go back to the beginning of therapy for hyperthyroidism and thyroid cancer with iodine radioisotopes in the 1940s<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>. However, its implementation in clinical practice is far from generalized as demonstrated in a European survey carried out in 2017<a class="elsevierStyleCrossRef" href="#bib0015">3</a>.In this sense, Spain is no exception, despite the RD 1841/1997 requiring estimation of the dose in “organs of special interest”; that is, to perform internal dosimetry. This obligation was updated in the 2013/59/Euratom Directive and its transposition in RD 601/2019, which establishes that “planning volumes be planned individually and be conveniently verified taking into account that the dose of healthy organs and tissues outside those considered in the planning should be as low as reasonably possible”.There is clearly an inexcusable legal obligation to perform internal dosimetry in all therapeutic procedures. Nonetheless, as in the rest of Europe, internal dosimetry is not routinely performed in clinical practice in our country. The main reason for this is the absence of clear evidence of the impact that internal dosimetry may have on the efficacy of treatment or the quality of life of the patients. To this we must add the increase in the complexity of the procedures, the human resources necessary and the length of equipment use as well as the inevitable need for collaboration with the Radiophysics Department. In 2017, the European Society of Nuclear Medicine (EANM) published a document that analyzed the feasibility of implementing treatment planning and verification procedures of the dose absorbed in the majority of treatments with RMT<a class="elsevierStyleCrossRef" href="#bib0020">4</a>. This document highlights the inevitable increase in resources required for systematic performance of internal dosimetry.To implement routine internal dosimetry it is necessary to provide clear evidence of the global benefits that our patients would obtain and that this compensates for the unavoidable increase in complexity and cost associated with this implementation. Nevertheless, to obtain clear evidence of this hypothetical benefit it is necessary to perform exhaustive studies of dose-effect relationships for which dosimetry must be performed. In addition, in order to provide dosimetric results that are reproducible and comparable among different centers, it is necessary to have standardized procedures with consensus by the different specialists and scientific societies involved. This would facilitate the practical performance of the calculations and diminish the uncertainties. With respect to these points, in the 2014 review by Strigari et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> evidence of a dose-effect correlation was found in a large part of the RMT treatments analyzed. Ideally, individualization of the activities to administer to each patient would allow increasing the dose absorbed in the tumors, and thereby increase the probability of therapeutic success while, at the same time, maintaining the dose in the organs at risk below the limits of toxicity<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a>.The objective of this work is to summarize the basic concepts of internal dosimetry and describe, step by step, its practical application in the treatment of neuroendocrine tumors with 177Lu-DOTATATE, according to our experience.Internal dosimetry: MIRD methodThe methodology most widely used for performing internal dosimetry calculations in RMT treatments is that proposed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine & Molecular Imaging (SNMMI)<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a>. According to the MIRD method, the mean dose absorbed in a target region (rT) due to the activity of the radiopharmaceutical present in different source regions (rS) is calculated using the following formula:<elsevierMultimedia ident="eq0005"></elsevierMultimedia>The term A˜(rS,TD) is the activity in the source region integrated over time; that is, it is the total number of decays produced in this region in the interval of temporal integration, TD. This interval covers the period of time from the point of radiopharmaceutical administration to the time this has completely disappeared from the source. Factor A˜(rS,TD) accounts for the temporal dependence of the problem; that is, the fact that the activity present in each source region changes over time.The term S(rT⟵rS) is the dose absorbed in the target region by unit of activity integrated over time in the source region. The S factors describe the physics of the transportation of radiation from the source region to the target region; that is, it accounts for the geometry of the problem. These are calculated using Monte Carlo methods and are tabulated for different energies<a class="elsevierStyleCrossRefs" href="#bib0055">11–13</a>. The summation of Eq. <a class="elsevierStyleCrossRef" href="#eq0005">(1)</a> allows several source regions to be included, the activity of which contributes to the dose absorbed in a determined target region.Based on what scale the source and target regions have been defined, we refer to dosimetry at the organ level, the voxel level or even to smaller scales<a class="elsevierStyleCrossRefs" href="#bib0070">14,15</a>. For example, in dosimetry at a voxel level, the source and target regions do not refer to organs but rather to voxels of the 3D image of the patient. The corresponding S factors are different in each case.Since the methodology of calculation at smaller scales is conceptually the same as at the organ level, this article describes the calculation methodology of the mean dose at the organ or tumor level because it is currently the most frequently used.Activity integrated over timeTo obtain the time-activity curve, the activity of each source region of the patient must be sampled; that is, measured at various times after administration. Depending on the case, the activity is measured by images in a gamma camera or a positron emission tomography/computerized tomography (PET/CT) scan using an external probe or taking a blood sample. The number of measurements and their temporal distribution should be chosen so that the adjustment curves reliably represents the real curve<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. The objective is to reproduce the real curve with the minimum number of measures possible to thereby limit the work load, the time of use of the gamma cameras and discomfort to the patient.A˜(rS,TD) is calculated from the time-activity graph as the area under the curve for a temporal interval TD. It can be determined by numerical integration or by analytical methods, after previously adjusting the data to a mathematical function<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a>.S factors at the organ levelThe S factors at the organ level are calculated by Monte Carlo methods in standard anthropomorphic phantoms<a class="elsevierStyleCrossRefs" href="#bib0055">11–13,19,20</a>. The S factors are tabulated and represent the dose absorbed in each target organ per unit of activity integrated over time in any other source organ of the phantom. In general, the greatest contribution to the dose absorbed in each organ presenting uptake is that due to the activity present in the organ itself (self-dose); in many cases, the dose due to the activity in other organs (cross-dose) can be obviated. In the case of tumors or metastasis that are not included in the standard phantoms, there are S factors tabulated for spherical masses of different volumes.The main limitation inherent to the MIRD methodology at the organ level is that it makes two suppositions:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1It assumes that the distribution of activity, and thus, the dose absorbed, is homogeneous in each organ; that is, it only allows calculating the average dose in each organ.</li><li class="elsevierStyleListItem" id="lsti0010">2It assumes that the geometry (the shape and relative positive of the organs) of the patient is identical to that of the standard phantom and, moreover, invariable along the treatment<a class="elsevierStyleCrossRef" href="#bib0105">21</a>.</li></ul>To overcome the limitation of these approaches, methods that calculate the dose absorbed at the voxel level (S-voxel factors and Monte Carlo calculations) over the image of each individual patient have been proposed<a class="elsevierStyleCrossRefs" href="#bib0110">22–24</a>. Although a priori these methods are more accurate, they are more computationally costly and do not always provide more accurate results, since in many cases the uncertainty is conditioned by the limited spatial resolution of the images<a class="elsevierStyleCrossRef" href="#bib0125">25</a>.Treatments with 177Lu-DOTATATE177Lu decays via β− to the fundamental state and to the three excited states of 177Hf, with a half-life of 6.647d<a class="elsevierStyleCrossRef" href="#bib0130">26</a>. The β− emissions deposit their energy locally and can be considered the main contribution to the therapeutic effect. The most abundant β− emission has a maximum kinetic energy of 498keV (probability 79 %), while the mean kinetic energy of all the β− particles emitted is 134keV. The maximum and mean ranges for β− emissions in soft tissue are 1.7mm and 0.23mm, respectively<a class="elsevierStyleCrossRef" href="#bib0135">27</a>. In turn, by decaying at lower energy levels, the photons emitted by 177Hf allow dosimetry based on images. The principal photopeaks of the spectrum of 177Lu are found at 113keV and 208keV (6.20 and 10.38 photons per 100 decays, respectively<a class="elsevierStyleCrossRef" href="#bib0130">26</a>). <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows a simplified scheme of 177Lu decay.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>177Lu-DOTATATE is a radiolabeled analog of somatostatin used in the treatment of patients with neuroendocrine tumors that are positive for receptors of this hormone. In 2005, the results of the first large clinical study on 177Lu-DOTATATE were published. The radioisotope was administered in fractionated form almost always in 4 cycles of 7.4GBq each, with 6–10 weeks between cycles<a class="elsevierStyleCrossRef" href="#bib0140">28</a>. No dose toxicity threshold was observed, and this fractionation scheme has been adopted since then, being considered as both safe and effective. This is currently the administration protocol recommended by the Spanish Agency of Medication and Health Care Products (AEMPS)<a class="elsevierStyleCrossRef" href="#bib0145">29</a>. The phase III NETTER-1 trial evaluated the safety and efficacy of 177Lu-DOTATATE in the treatment of neuroendocrine tumors of metastatic midgut intestine<a class="elsevierStyleCrossRef" href="#bib0150">30</a>. The trial demonstrated that the use of this radiopharmaceutical increased progression-free time and overall survival compared with unlabeled somatostatin and resulted in the registry of the radiopharmaceutical known today in the market as Lutathera®<a class="elsevierStyleCrossRef" href="#bib0155">31</a>.Dosimetry in treatments with 177Lu-DOTATATEPlanning dosimetry can be done in RMT after injecting a tracing activity of the radiopharmaceutical (pretreatment planning) or during the treatment after administering the therapeutic activity of the radiopharmaceutical (peritreatment dosimetry). In pretreatment dosimetry, the activity needed to obtain a target dose absorbed is calculated<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a>. In peritreatment dosimetry, the dose absorbed in determined volumes of interest (VOI) after the administration is calculated. In treatments with 177Lu-DOTATATE the VOI are the primary tumor, if it can be identified, and the metastases, which are mainly hepatic, as well as the kidneys and bone marrow<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a> are the organs at risk. In treatments fractionated in several cycles, the peritreatment dosimetry of the first cycle can also be used to calculate the activity to administer to achieve a target dose in the later cycles. Given the fixed administration schedule established by AEMPS for 177Lu-DOTATATE (4 cycles of 7.4GBq), the dosimetric procedures with this radioisotope are limited to peritreatment dosimetry without the possibility of varying the activity in posterior cycles to the first. Nonetheless, in clinical trials dosimetry has been used in the first treatment cycles to predict the dose in the following cycles and, thus, calculate the maximum number of cycles of 7.4GBq that can be given to a determined patient before achieving the dose of toxicity in the organs at risk<a class="elsevierStyleCrossRefs" href="#bib0180">36,37</a>.The methodology for the calculation of the dose absorbed in 177Lu-DOTATATE is described below, divided into three sections. First, the method to measure the activity is each of the source regions (quantification of activity) is described. Secondly, the number of times and at what time this activity is measured in each source region is specified as well as how to obtain the time-activity curve from which the activity integrated over time is calculated (sampling of the activity and calculation of the time-activity curve). Lastly, once the activity integrated over time in each source region and the S factors are known, the tables are taken and the dose absorbed in each target region is calculated (calculation of dose absorbed). Note that the source and target regions do not have to coincide: there are source regions which uptake activity in which, however, it is of no interest to know the dose absorbed (see <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The source regions in these treatments are the tumors and the metastases (lesions) as well as the kidneys, spleen, and bone marrow. In addition, the component of the rest of the body is also considered the source region which includes the whole body, excluding these organs. The target regions are the previously mentioned VOI; that is, the lesions and organs at risk (kidneys and bone marrow). Both the target regions and the organs at risk should be defined by the nuclear medicine physician before each treatment.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Quantification of activityQuantification of activity in solid organs and lesions based on SPECT/CT imagesThe emission of photons of 177Lu allows measuring the activity present in different zones of the body from images taken with a gamma camera. In principle, planar or tomographic images (SPECT/CT) can be used or a hybrid methodology can be applied in which several planar images are acquired to obtain a relative time-activity curve and a SPECT/CT image to normalize this curve<a class="elsevierStyleCrossRefs" href="#bib0185">37–40</a>. In general, the choice of one modality or another depends on the means available in each installation. Nevertheless, in treatments with 177Lu-DOTATATE the preferred method for dosimetry in both the kidneys<a class="elsevierStyleCrossRef" href="#bib0205">41</a> and in tumors or metastases is only based on SPECT/CT images, because it provides more exact quantification<a class="elsevierStyleCrossRefs" href="#bib0085">17,42,43</a> and is not limited by the overlapping of tissues inherent to planar acquisitions.Characterization of the gamma cameraTo be able to quantify the activity of the radioisotope with SPECT/CT images, previous characterization of the gamma camera is necessary. Firstly, the calibration factor (Fcal) must be obtained to convert the count rate measured into activity. In addition, the recovery factors must be determined to correct the partial volume effect (PVE) and, lastly, characterize the dead time of the gamma camera.Calibration factorCalibration of the gamma camera consists in obtaining the count rate detected per unit of activity of the radioactive source; that is, calculate its sensitivity. The calibration factor Fcal is usually measured in counts per second per MBq (cps/MBq), and to obtain this an image of a phantom with known activity must be acquired, preferably in the same conditions of acquisition and reconstruction as that used in clinical practice. There are different options when choosing the geometry of the calibration phantom. The most common are: point source, Petri dish and cylindrical source<a class="elsevierStyleCrossRefs" href="#bib0220">44–50</a>.To obtain a calibration factor for SPECT/CT images D’Arienzo et al.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> compared 4 different geometries: a point source in air, a 16ml sphere in air, a 16ml sphere in water and a cylinder. They obtained slightly worse results for the point source, but the errors in quantification were less than 10% of all the cases. In turn, Mezzenga et al.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> compared a 16ml sphere in water with a cylinder phantom and concluded that cylindrical geometry may be the best option because it minimizes the PVE in the calibration acquisitions.Partial volume effectThe PVE is defined as the apparent reduction of the concentration of activity in a region of uptake due to the limited spatial resolution of the image system<a class="elsevierStyleCrossRef" href="#bib0255">51</a>. This effect mainly appears as a consequence of the detector-collimator effect (explained in the section on Image processing and analysis), although it is also due to the structure of the voxels used to represent the images not coinciding with shape of the organs and the structures visualized. With this, the voxels of the borders between regions have a value of intermediate activity between the activities of the two adjacent regions, creating a twilight effect in the image<a class="elsevierStyleCrossRef" href="#bib0260">52</a>. The PVE affects both the activity measured in a VOI and its volume. It depends on the characteristics of the imaging system, the distribution of activity and the shape and volume of the VOI<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, the smaller the volume of the VOI the more evident the PVE.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>To correct this effect the usual method consists in using a phantom of spheres of different volumes in which a known concentration of 177Lu activity has been injected Areal. Afterwards, SPECT/CT images of the phantom are obtained from which the concentration of activity measured in each sphere is obtained Ameasured. To determine Ameasured in each sphere, the surface delimiting the fluid with the activity of 177Lu is delineated slice by slice over the CT image. Ideally, the volume delimited by this surface should coincide with the real volume of fluid injected into each sphere. The count rate corresponding to the fluid in each sphere is obtained from the SPECT image, and by dividing the count rate by the calibration factor Fcal you obtain the mean activity. The Ameasured concentration is determined as the ratio between this activity measured and the volume calculated in the CT image. Finally, the recovery coefficient (RC)<a class="elsevierStyleCrossRefs" href="#bib0085">17,43,51–53</a> is obtained and is defined as the relation between the concentration of activity measured Ameasured and the concentration of real activity Areal:<elsevierMultimedia ident="eq0010"></elsevierMultimedia>The  RC can be obtained for any VOI in the patients by representing the RC values based on the volumes (or the diameter) of the spheres and adjusting the point obtained to a curve<a class="elsevierStyleCrossRefs" href="#bib0265">53,54</a>. <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a> shows a phantom of spheres for calculating the RC.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Dead timeIdeally, the count rate detected by the gamma camera is proportional to the activity, maintaining the sensitivity (cps/MBq) of the system constant. However, the gamma camera acts as a paralyzable system<a class="elsevierStyleCrossRef" href="#bib0270">54</a> and for elevated count rates some events can be lost because the detector needs time (short, but not null) to process each event detected during which it cannot detect another count. Therefore, for high activities a reduction in sensitivity is observed due to the dead time of the gamma camera. This effect is especially important for isotopes that have many photon emissions, such as 131I, or in early acquisitions since, in these cases, the count rates are higher.Given the characteristics of 177Lu emission<a class="elsevierStyleCrossRef" href="#bib0130">26</a>, it is very unlikely for saturation effects of the detector of the gamma camera and loss of counts due to dead time to be produced in the clinical acquisitions except for acquisitions made during the first hours after administration. Therefore, it is not necessary to apply correction for dead time in acquisitions made the day after administration<a class="elsevierStyleCrossRef" href="#bib0275">55</a>. Nonetheless, some authors have measured losses by dead time in the first clinical acquisition in some patients treated with 177Lu-DOTATATE, and have proposed different methods for correcting for this effect<a class="elsevierStyleCrossRefs" href="#bib0280">56–58</a>. Losses by dead time in these studies were modest and were due to the first acquisition being made within the first 4h after administration when the count rates were elevated.Acquisition of imagesTo quantify the activity of 177Lu with SPECT images, the MIRD committee recommends acquiring an energy window of 15%–20% centered on the photopeak of 208keV and with collimators of mean energy (ME)<a class="elsevierStyleCrossRef" href="#bib0275">55</a>. The combination of ME collimators with the photopeak of 208keV presents a greater relation of primary photons versus scattered photons; that is, less contribution of scattered radiation (see <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>) and, thus, greater contrast in the images<a class="elsevierStyleCrossRef" href="#bib0275">55</a>. In general, it is recommended to use matrices of 128×128, but a matrix of 64×64 could be used for low count rates<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. With regard to the number of projections, a range of projections of between 60 and 120 has been used in clinical studies with SPECT images<a class="elsevierStyleCrossRef" href="#bib0275">55</a>. The projection time may vary based on the count rate, which, in turn, depends on the percentage of uptake and the time after administration. Nonetheless, to minimize patient discomfort and thereby reduce movement artefacts, it is recommended to limit the total time of the SPECT acquisition to 30minutes<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. This implies that the time per projection should be less according to an increase in the number of projections. Finally, the use of orbits with self-contouring is recommended so that the collimators can be as close as possible to the patient and thereby obtain the best spatial resolution possible<a class="elsevierStyleCrossRef" href="#bib0275">55</a>.<elsevierMultimedia ident="fig0025"></elsevierMultimedia>The recommended number of acquisitions is described in the section on Sampling of the activity and calculation of the time-activity curve.Image processing and analysisWhen reconstructing the SPECT image a series of factors which degrade the image and reduce the accuracy of the quantification of activity must be corrected. An iterative method is recommended to perform the reconstruction, because it allows correcting some of the effects which degrade the image in the process<a class="elsevierStyleCrossRefs" href="#bib0085">17,55</a>. The optimal number of iterations and subsets to use depends on the gamma camera. The selection of the optimum value of these parameters should be determined during the characterization of the equipment by comparison of the images of the phantoms acquired with different technical conditions<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. The introduction of a filter in the reconstruction process can reduce the noise and improve the quality of the image, but it can also affect the quantification and, thus, it is not always recommendable in dosimetry acquisitions. It must be ensured that the filtrate does not affect the accuracy of the quantification<a class="elsevierStyleCrossRefs" href="#bib0085">17,55</a>. The same acquisition may be valid for the medical diagnosis and for dosimetry, using the appropriate parameters of reconstruction in each case. Below, the principal effects which degrade the projections acquired are summarized.AttenuationThe flow of photons of 208keV is reduced to half with a soft tissue thickness of 5cm; that is, the attenuation in the patient has an important effect on the number of photons that reach the gamma camera<a class="elsevierStyleCrossRef" href="#bib0275">55</a>. The grade of attenuation depends on the position from which the photons are emitted and the different densities of tissue through which they pass inside the patient. It is therefore important to obtain a specific attenuation map for each patient<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. There are several methods to obtain this map, the most accurate being that which uses the information of the CT image of the SPECT/CT equipment. After obtaining the map and correcting for the attenuation corresponding to the energy of 177Lu, the number of counts of each voxel of the SPECT image is corrected by attenuation.Scattered radiationScattered radiation is formed by secondary photons which are detected in the photopeak window after having undergone one or more scattering events in the tissue and/or the collimator, and which, thus, generate counts in positions and energies different from those of the original photon. The proportion of scattered photons detected in the acquisition window mainly depends on the width of the window of the photopeak, the energy of the photons, the distance they travel within the patient and the coefficient of attenuation of the tissue they pass through (air, bone…)<a class="elsevierStyleCrossRef" href="#bib0295">59</a>. In the acquisition of 177Lu with the ME collimator, this proportion is of around 20%–30% of the total photons that reach the detector<a class="elsevierStyleCrossRef" href="#bib0275">55</a>.To correct for the effect of scattered radiation, the method most used is the triple energy window (TEW) method<a class="elsevierStyleCrossRef" href="#bib0300">60</a>, which uses the counts acquired in the two windows of the spectrum at both sides of the photopeak and estimates the component of scattered radiation in the photopeak making a trapezoidal approach. A variation is the double energy window (DEW) method<a class="elsevierStyleCrossRef" href="#bib0305">61</a>, which uses a single scatter radiation window to the left of the photopeak and is applied in cases in which the component of scattered radiation in the upper window is null or very low<a class="elsevierStyleCrossRef" href="#bib0295">59</a>. This is the case of 177Lu when ME collimators are used<a class="elsevierStyleCrossRefs" href="#bib0280">56,62</a>, provided that the count rates are not excessively high<a class="elsevierStyleCrossRefs" href="#bib0250">50,58</a>.Collimator-detector responseCollimator-detector response makes the image of a specific object appear blurry, affecting not only the quality of the image but also the accuracy of the quantification of activity. Its importance increases with the distance to the collimator<a class="elsevierStyleCrossRef" href="#bib0295">59</a>. Collimator-detector response is made up of four components. The first is associated with the intrinsic response of the detector which has a certain spatial resolution. The second is the geometric component of the collimator: although the holes of the collimators of the gamma cameras are narrow, it is possible for photons that arrive with a certain angle of incidence to pass through and reach the detector. This increases the uncertainty of the positioning of the radioactive events that generated those photons. The third component is due to the scattering events mainly occurring in the collimator. Finally, the fourth component is due to the possibility that some very energetic photons penetrate the septa of the collimators (component of septal penetration)<a class="elsevierStyleCrossRef" href="#bib0085">17</a>. Each of these four components is shown in <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>. To correct for the intrinsic response of the detector and the geometric component of the collimator, the point spread function (PSF) is used in the reconstruction process<a class="elsevierStyleCrossRef" href="#bib0315">63</a>. The correction of the scatter component in the collimator is included in the method of scattering correction mentioned in the previous section. Finally, Monte Carlo simulations can be performed or modified PSFs can be applied to correct the septal penetration<a class="elsevierStyleCrossRef" href="#bib0320">64</a>.<elsevierMultimedia ident="fig0030"></elsevierMultimedia>Activity in each VOIThe activity present in each region of interest of the image is quantified by the count rates in this zone, applying the pertinent corrections as in the following equation:<elsevierMultimedia ident="eq0015"></elsevierMultimedia>CVOI is the count rate measured in VOI corrected during the reconstruction for the effects of attenuation, disperse radiation and collimator-detector. To correct these three effects, the methods most commonly used are, respectively, the CT attenuation map, the TEW method and the PSF. Fcal is the calibration factor, RC is the recovery coefficient corresponding to the volume of the VOI and DTF is the correction factor for dead time in each VOI.As explained previously, correction for dead time is not necessary for images of 177Lu acquired after the day following the administration of the radiopharmaceutical.Quantification of activity in bone marrowIn RMT treatments the dose absorbed in bone marrow is considered to have three components: that due to the activity present in the bone marrow itself, that due to the activity present in other organs with physiological uptake and that due to the activity present in the rest of the body<a class="elsevierStyleCrossRef" href="#bib0325">65</a>. In treatments with 177Lu-DOTATATE, the contribution to the dose absorbed due to the activity present in the organs with greatest physiological uptake and in the rest of the body is estimated at between 15% and 68%, and should not be disregarded<a class="elsevierStyleCrossRefs" href="#bib0180">36,66,67</a>.To determine the activity present in the bone marrow itself the concentration of activity in blood is measured. The most common method to do this is with a duly calibrated gamma counter (well type) of NaI (T1) (although a beta counter or a semiconductor detector can also be used<a class="elsevierStyleCrossRef" href="#bib0325">65</a>).To quantify activity in the rest of the body the activity in the whole body is measured and then the contributions of the bone marrow and the organs with physiological uptake obtained in SPECT/CT images are subtracted.Characterization of the equipmentThe response of the well counter in which the blood samples of the patients are measured should be well characterized, and this means that the calibration factor for the energy of 177Lu must be known and the appropriate corrections for dead time and geometry must be applied<a class="elsevierStyleCrossRef" href="#bib0340">68</a>. To obtain a calibration factor, a certain volume can be extracted from a source of calibrated 177Lu <a class="elsevierStyleCrossRefs" href="#bib0180">36,68</a> (e.g. that used for the calibration of the activimeter). The activity extracted is measured in the activimeter and is used to prepare an aqueous solution of 177Lu, from which an aliquot is extracted to obtain the calibration factor of the counter. The use of a precision balance can help to achieve greater accuracy in the value of weight and, thus, of the concentration of the solution. The activity of the aliquot extracted from the solution should be sufficiently low to be able to avoid losses by dead time in the well counter. In addition, to eliminate the need for geometric corrections, the aliquot can be prepared with the same geometry (identical recipient, same volume) with which the patient blood samples are prepared. The calibration factor of the well counter is the count rate measured divided by the activity of the aliquot.Acquisition of measurementsThe measurement of the concentration of activity in blood is made in volumes of 1 or 2ml, obtained from the blood samples of the patient extracted from the contralateral arm of the administration of the radiopharmaceutical to avoid contamination. The number of samples recommended is described in the section on Sampling of activity and calculation of the time-activity curve. It is recommended to measure all the samples on the same day and apply the corresponding correction for the physical decay of 177Lu.Activity in bone marrowWhen there is no specific uptake of activity in the bone marrow cells as in the case of treatments with 177Lu-DOTATATE<a class="elsevierStyleCrossRef" href="#bib0330">66</a>, it is assumed that the concentration of activity in bone marrow Arm is proportional to the concentration of activity in blood  Abl<a class="elsevierStyleCrossRef" href="#bib0345">69</a>:<elsevierMultimedia ident="eq0020"></elsevierMultimedia>where the constant RMBLR (red marrow to blood level ratio) is the ratio of concentrations of activity in bone marrow and in blood. In radioimmunotherapy RMBLR values have been obtained with different isotopes ranging from 0.2 up to 0.4<a class="elsevierStyleCrossRefs" href="#bib0345">69,70</a>. In regard to treatments with somatostatin peptide analogs, Forrer et al.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> performed bone marrow aspirates together with blood extractions in a total of 15 patients treated with [177Lu-DOTA0,Tyr3]octreotate, and obtained a RMBLR value ≅1; that is, they concluded that the concentration of activity present in the red marrow is equal to the concentration of activity present in blood.Using Eq. <a class="elsevierStyleCrossRef" href="#eq0020">(4)</a> and a RMBLR value=1, the following Formula <a class="elsevierStyleCrossRef" href="#eq0025">(5)</a> for activity in bone marrow is obtained:<elsevierMultimedia ident="eq0025"></elsevierMultimedia>where mrm,pat is the mass of the bone marrow of the patient that is calculated by linearly scaling the mass of the bone marrow of the standard phantom mrm,phan by the mass of the whole body of the patient mwb,pat and the phantom mwb,phan; that is, applying a rule of three as shown in Eq. <a class="elsevierStyleCrossRef" href="#eq0030">(6)</a><a class="elsevierStyleCrossRef" href="#bib0355">71</a>. The masses of the phantom are tabulated in ICRP 110<a class="elsevierStyleCrossRef" href="#bib0100">20</a>.<elsevierMultimedia ident="eq0030"></elsevierMultimedia>Therefore, to quantify Arm blood samples are taken from the patient and the concentration of activity is measured in the well counter. In addition to this method, based on measuring activity concentrations in blood, there are proposals based on quantification with images<a class="elsevierStyleCrossRefs" href="#bib0335">67,72,73</a>. Quantifying the concentration of activity in bone marrow from images may be useful when the patient presents bone metastases with significant uptake, given that in these cases the blood sample method would underestimate the dose absorbed in the bone marrow.Quantification of whole body activityWhole body activity can be measured by the acquisition of a whole body scan in a gamma camera. However, a simpler practical option is to use an external probe which can be a gaseous detector (ionization camera or Geiger–Müller) or scintillation crystal<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. The option of the external probe has an important advantage and it is that the measures performed are much more rapid and do not require gamma camera time. Thus, more measures can be made and thus there are more points when adjusting the time-activity curve<a class="elsevierStyleCrossRef" href="#bib0370">74</a>.Characterization of the equipmentThe external probe used to measure whole body activity should be calibrated and certified by an accredited calibration laboratory and characterized for measuring count rates of the energy of the photons emitted by 177Lu and for the range of activities of the treatments with 177Lu-DOTATATE<a class="elsevierStyleCrossRefs" href="#bib0295">59,74</a>.Acquisition of the measuresFor whole body measurements, the first acquisition with the external probe should always be made immediately after the administration and before the patients has excreted activity. This allows the conversion factor to be obtained which relates the magnitude measured by the probe (cps, μSv/h, etc.) with the activity present in the body of the patient which is known in the first moment (real activity administered, calculated from the measurements of the full and empty vial in the activimeter). The remaining acquisitions are always made after the patient has urinated so that the content of the bladder does not distort the results<a class="elsevierStyleCrossRef" href="#bib0325">65</a>. The recommended number of measures is described in the section on Sampling of the activity and calculation of the time-activity curve. Special care should be made to always reproduce the same geometry. To minimize the effect that the attenuation of the patients themselves might have on the result of the acquisitions, each acquisition should have two measures, one anterior (AP) and anther posterior (PA), both with the probe at the same distance from the patient<a class="elsevierStyleCrossRef" href="#bib0325">65</a> (see <a class="elsevierStyleCrossRef" href="#fig0035">Fig. 7</a>).<elsevierMultimedia ident="fig0035"></elsevierMultimedia>Whole body activityWhole body activity at each time t is the geometric measure of the two measures taken with the external probe (AP and PA), corrected by the conversion factor<a class="elsevierStyleCrossRef" href="#bib0325">65</a>:<elsevierMultimedia ident="eq0035"></elsevierMultimedia>where A0 is the activity administered, CAP,t and CPA,t are the anterior (AP) and posterior (PA) measures of the probe at the time t and CAP,0 and CPA,0 are the anterior (AP) and posterior (PA) measures of the probe at the time of administration (t=0).Sampling of the activity and calculation of the time-activity curveTo reduce the uncertainties in the adjustment of the data to a curve, a minimum of three measures per each phase of the kinetics of the radiopharmaceutical is recommended<a class="elsevierStyleCrossRefs" href="#bib0080">16,64,73</a>. The optimal times to perform the acquisitions depends on the effective elimination time of the radiopharmaceutical in each tissue (Te). It is generally recommended to make one or two acquisitions at some fraction of Te, another around Te and another, or two last acquisitions after 3–5 times Te<a class="elsevierStyleCrossRef" href="#bib0080">16</a>. It is important to conveniently characterize the last retention phase which presents the greatest contribution to the activity integrated over time<a class="elsevierStyleCrossRef" href="#bib0385">77</a>. To obtain the activity integrated over time from the data obtained any integration method can be used (trapezoidal method or analytical integration after adjusting the data to an exponential or sum of exponentials).Solid organs and lesionsTwo phases can be identified in the kinetics of 177Lu-DOTATATE<a class="elsevierStyleCrossRef" href="#bib0155">31</a>. The first is rapid elimination from the blood and uptake in organs that lasts an average of 4h<a class="elsevierStyleCrossRef" href="#bib0155">31</a>, and the second is of slow elimination which may approximate a simple exponential<a class="elsevierStyleCrossRef" href="#bib0090">18</a>. On having two phases, in theory a minimum of six measures of the activity in organs should be made to correctly sample the time-activity curve<a class="elsevierStyleCrossRef" href="#bib0090">18</a>. However, since the uptake phase is very short, the activity in the organs of interest changes very rapidly, and the measures of activity can, as a result, give distorted data. Therefore, in practice it is acceptable to assume instantaneous uptake and sample only the elimination phase<a class="elsevierStyleCrossRef" href="#bib0090">18</a>. To do this, three SPECT/CT acquisitions should be made. Since the Te is not known a priori and, in addition, it is different for the different tissues, the literature describes different sampling schemes. For example, Sandström et al.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> and Garske et al.<a class="elsevierStyleCrossRef" href="#bib0390">78</a> acquire images at 24, 72 and 168h post-administration. Other groups<a class="elsevierStyleCrossRefs" href="#bib0385">77,79,80</a> acquire images at around 4, 24 and 72h post-administration. Santoro et al.<a class="elsevierStyleCrossRef" href="#bib0405">81</a> propose four measurement points: at 4, 24, 72 and 192h. Different attempts have been made to reduce the number of SPECT/CT acquisitions necessary for the dosimetry to solid organs and lesions, although most are limited to renal dosimetry<a class="elsevierStyleCrossRefs" href="#bib0390">78,82–84</a>. Freedman and cols<a class="elsevierStyleCrossRef" href="#bib0425">85</a> compared the results of doses to solid organs and lesions obtained at 4, 3 and 2 sampling points. They concluded that three SPECT/CT (at 24, 72 and 168h post-administration) provide a good estimation of the dose absorbed. The method based on two SPECT/CT is also feasible, although it would increase the uncertainty of the results.Blood177Lu-DOTATATE is intravenously administered and is rapidly eliminated from the blood, counting its kinetics in two phases of elimination<a class="elsevierStyleCrossRef" href="#bib0180">36</a>. Therefore, for sampling the time-activity curve and following the recommendations of the EANM<a class="elsevierStyleCrossRefs" href="#bib0325">65,75</a>, at least six blood samples of the patients should be taken in the first 24h, and it would be recommendable to take at least one more in the delayed phase between 24h and 168h post-administration<a class="elsevierStyleCrossRef" href="#bib0180">36</a>.Whole bodyIt has been observed that the kinetics of 177Lu-DOTATATE in the whole body can also be described by two phases of elimination, a first rapid phase in the first 24h and a second slower phase thereafter<a class="elsevierStyleCrossRef" href="#bib0180">36</a>. Therefore, at least 6 measures must be made during the first week after administration, the 3 or 4 first measures within 24h for conveniently sampling the two phases of elimination.After having obtained the activities integrated over time in the whole body, bone marrow and in solid organs, the activity integrated over time in the remainder of the body is calculated by the following Eq. <a class="elsevierStyleCrossRef" href="#eq0040">(8)</a>.<elsevierMultimedia ident="eq0040"></elsevierMultimedia>A˜rb is the activity integrated over time in the remainder of the body, A˜wb is the activity integrated over time in the whole body, A˜rm is the activity integrated over time in red marrow and A˜h is the activity integrated over time in the organ h with physiological uptake.Calculation of the dose absorbedOnce the activity integrated over time in the main VOI is known, the dose absorbed is calculated by applying Eq. <a class="elsevierStyleCrossRef" href="#eq0005">(1)</a> of the MIRD method. The S factors associated with the term of self-dose of an organ h (in which β emissions dominate) are usually linearly scaled to the mass of the organ of the patient<a class="elsevierStyleCrossRef" href="#bib0430">86</a>, while the S factor associated with terms of cross-dose of an organ i to another organ h (due to γ emissions) is considered independent of the mass<a class="elsevierStyleCrossRefs" href="#bib0325">65,87</a>. Therefore:<elsevierMultimedia ident="eq0045"></elsevierMultimedia>where mh,phan and mh,pat are the masses of organ h of the reference phantom and the organ h of the patient, respectively.Solid organs and lesionsTo calculate the dose absorbed in solid organs and lesions (primary tumor or metastasis) we must, on one hand, calculate the dose due to the activity present in the organ or lesion itself (self-dose) and the cross-dose, on the other hand, of any organ that accumulates radiotracer and the emission of which can reach the kidneys or the lesions. Thus, following the MIRD methodology, the dose absorbed in kidneys and spleen is calculated with the following formulas<a class="elsevierStyleCrossRef" href="#bib0045">9</a>:<elsevierMultimedia ident="eq0050"></elsevierMultimedia>However, as mentioned previously, in most of the cases, the principal contribution to the dose absorbed is that due to the activity in the organ itself, and it can be reasonably assumed that the cross components are negligible (the factors Skidneys⟵spleen and Sspleen⟵kidneys are three orders of magnitude inferior to the factors Sspleen⟵spleen and Skidneys⟵kidneys). It should be taken into account that although the spleen is an organ with physiological uptake, it is not usually considered an organ at risk in these treatments<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a>.To determine the dose absorbed in the lesion (tumor or metastasis),  Dlesion, only the dose due to the activity present in the lesion itself (self-dose) is considered:<elsevierMultimedia ident="eq0055"></elsevierMultimedia>In this case Sspherical,vol is the S factor corresponding to a sphere with a volume equal to that of the lesion, interpolated from the tables obtained with Monte Carlo for the emmission energies of the radioisotope.Bone marrowAs explained previously, the dose absorbed in the bone marrow has three components so that the general MIRD equation (Eq. <a class="elsevierStyleCrossRef" href="#eq0005">(1)</a>) remains as follows in this case:<elsevierMultimedia ident="eq0060"></elsevierMultimedia>The factors Srm⟵rm and Srm⟵h are tabulated for standard phantoms<a class="elsevierStyleCrossRef" href="#bib0440">88</a>. To calculate those corresponding to the patient they must be scaled according to Eq. <a class="elsevierStyleCrossRef" href="#eq0045">(9)</a>. The factor Srm⟵rb is not tabulated since the component of the remainder of the body depends on what organs are to be treated and this is calculated with the following Eq. <a class="elsevierStyleCrossRef" href="#eq0065">(13)</a><a class="elsevierStyleCrossRefs" href="#bib0325">65,87</a>:<elsevierMultimedia ident="eq0065"></elsevierMultimedia>where the subindices rm, wb, rb and h are red marrow, whole body, remainder of the body and “other organs”, respectively, and the subindices phan and pat refer to the phantom and patient, respectively. Direct measurement of the mass of the red marrow of the patient is not possible, and it is therefore calculated from the mass of the red marrow of the standard phantom with Eq. <a class="elsevierStyleCrossRef" href="#eq0030">(6)</a><a class="elsevierStyleCrossRef" href="#bib0355">71</a>.Uncertainties in the calculationsAll the numerical calculations made from experimental data have an uncertainty associated, and dosimetry calculations are no exception<a class="elsevierStyleCrossRefs" href="#bib0445">89,90</a>. In 2011, Lassmann et al.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> described the need to evaluate the uncertainties in the measures and the calculations of internal dosimetry as a fundamental part of the scientific analysis.In a complete internal dosimetry calculation there are many sources of uncertainty to consider, and detailed quantification of all of these uncertainties is a laborious process. To perform the calculation, the uncertainties associated with the final dose can be divided into two groups: those associated with the activity integrated over time and those that affect the geometric factors of the problem. The uncertainties of the first group depend on the method used to measure the activity (planar images, SPECT/CT, external probe, etc.) of the data sample performed (the number of acquisitions and the time at which they were made) and the method of integration. The uncertainties of the second group depend on the dosimetric method used (MIRD at an organ level, MIRD at a voxel level, Monte Carlo). Obviously, to evaluate the uncertainty of the final dose both groups should be considered.One would think that as the calculations are refined and the scales worked with are smaller and increasingly more based on the particular characteristics of each patient, going from MIRD at an organ level to MIRD at a voxel level and afterwards to the Monte Carlo calculation, the uncertainty in the absorbed dose would be increasingly less. However, due to the limited spatial resolution of the gamma cameras, the uncertainties in the quantification of the activity may be greater than the uncertainty associated with the dosimetric method used, especially in very small lesions<a class="elsevierStyleCrossRef" href="#bib0455">91</a>, making, in some cases, the investment in calculations more exact, but computationally more costly, unjustified<a class="elsevierStyleCrossRef" href="#bib0460">92</a>.In 2018, the EANM published guidelines for the analysis of uncertainties in the calculations of RMT doses based on the MIRD method<a class="elsevierStyleCrossRef" href="#bib0380">76</a>. They analyze the multiplication of uncertainties along the whole dosimetric calculation chain until the mean dose absorbed in each VOI and its uncertainty are obtained. The document presents an example of a patient who received 90Y-DOTATATE for treatment and 111In-DOTATATE for images. It calculated the dose absorbed and the uncertainties in lesions, kidneys, liver and spleen and obtained uncertainty of around 35% in the lesions, being less in the remaining regions. Following the methodology proposed by this guideline, in 2020 Finocchiaro et al.<a class="elsevierStyleCrossRef" href="#bib0465">93</a> carried out an analysis of uncertainties in a total of 154 lesions from 49 patients receiving RMT. They obtained a wide range of uncertainties (14%–102%) and identified the principal source as the uncertainty in the volume of each VOI, associated with the delineation process.In the particular case of dosimetry to the kidneys in treatments with 177Lu-DOTATATE, Gustafsson et al.<a class="elsevierStyleCrossRef" href="#bib0470">94</a> analyzed uncertainties in a virtual patient model. With this model they identified the main sources of uncertainties as those associated with the calibration factor and the coefficients of recovery corrected by PVE.In the end, the uncertainty in the calculation of internal dosimetry should appear in the dosimetry report, and it is important to consider it when evaluating each dose result<a class="elsevierStyleCrossRef" href="#bib0375">75</a>.ConclusionsDosimetry in treatments with 177Lu-DOTATATE is divided into dosimetry of lesions and dosimetry of organs at risk (bone marrow and kidneys).Dosimetry requires previous characterization of the equipment for making the measurements: gamma camera, well counter and external probe. Characterization of the gamma camera involves several acquisitions with different phantoms and requires a source of 177Lu with known activity.To make a complete dosimetry calculation at least three SPECT/CT acquisitions are necessary as well as six blood extractions and 6 whole body measures of the patient during the first week after administration. This represents an increase in the work load and patient discomfort. However, these procedures should be assumable by most services with RMT units.The methodology of dosimetric quantification described in the present article allows estimating the absorbed dose in 177Lu-DOTATATE treatments and, thus, fulfill the 2013/59/Euratom Directive. Therefore, it is possible and necessary to modify the protocols of routine work procedures of the therapeutic services of Nuclear Medicine to include dosimetry calculations which will improve both their efficacy and safety.Conflict of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1502251" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1363377" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1502250" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1363376" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Internal dosimetry: MIRD method" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Activity integrated over time" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "S factors at the organ level" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatments with Lu-DOTATATE" ] 7 => array:3 [ "identificador" => "sec0030" "titulo" => "Dosimetry in treatments with Lu-DOTATATE" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0035" "titulo" => "Quantification of activity" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0040" "titulo" => "Quantification of activity in solid organs and lesions based on SPECT/CT images" "secciones" => array:4 [ 0 => array:3 [ "identificador" => "sec0045" "titulo" => "Characterization of the gamma camera" "secciones" => array:3 [ 0 => array:2 [ …2] 1 => array:2 [ …2] 2 => array:2 [ …2] ] ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Acquisition of images" ] 2 => array:3 [ "identificador" => "sec0070" "titulo" => "Image processing and analysis" "secciones" => array:3 [ 0 => array:2 [ …2] 1 => array:2 [ …2] 2 => array:2 [ …2] ] ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Activity in each VOI" ] ] ] 1 => array:3 [ "identificador" => "sec0095" "titulo" => "Quantification of activity in bone marrow" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0100" "titulo" => "Characterization of the equipment" ] 1 => array:2 [ "identificador" => "sec0105" "titulo" => "Acquisition of measurements" ] 2 => array:2 [ "identificador" => "sec0110" "titulo" => "Activity in bone marrow" ] ] ] 2 => array:3 [ "identificador" => "sec0115" "titulo" => "Quantification of whole body activity" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0120" "titulo" => "Characterization of the equipment" ] 1 => array:2 [ "identificador" => "sec0125" "titulo" => "Acquisition of the measures" ] 2 => array:2 [ "identificador" => "sec0130" "titulo" => "Whole body activity" ] ] ] ] ] 1 => array:3 [ "identificador" => "sec0135" "titulo" => "Sampling of the activity and calculation of the time-activity curve" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0140" "titulo" => "Solid organs and lesions" ] 1 => array:2 [ "identificador" => "sec0145" "titulo" => "Blood" ] 2 => array:2 [ "identificador" => "sec0150" "titulo" => "Whole body" ] ] ] 2 => array:3 [ "identificador" => "sec0155" "titulo" => "Calculation of the dose absorbed" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0160" "titulo" => "Solid organs and lesions" ] 1 => array:2 [ "identificador" => "sec0165" "titulo" => "Bone marrow" ] ] ] ] ] 8 => array:2 [ "identificador" => "sec0170" "titulo" => "Uncertainties in the calculations" ] 9 => array:2 [ "identificador" => "sec0175" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0180" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-01-15" "fechaAceptado" => "2021-02-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1363377" "palabras" => array:3 [ 0 => "Internal dosimetry" 1 => "Radionuclide therapy" 2 => "177Lu-DOTATATE" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1363376" "palabras" => array:3 [ 0 => "Dosimetría interna" 1 => "Terapia radiometabólica" 2 => "177Lu-DOTATATE" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Implementation of dosimetry calculations in the daily practice of Nuclear Medicine Departments is, at this time, a controversial issue, partly due to the lack of a standardized methodology that is accepted by all interested parties (patients, nuclear medicine physicians and medical physicists). However, since the publication of RD 601/2019 there is a legal obligation to implement it, despite the fact that it is a complex and high resource consumption procedure. The aim of this article is to review the theoretical bases of in vivo dosimetry in treatments with 177Lu-DOTATATE. The exposed methodology is the one proposed by the MIRD Committee (Medical Internal Radiation Dose) of the SNMMI (Society of Nuclear Medicine & Molecular Imaging). According to this method, the absorbed dose is obtained as the product of 2 factors: the time-integrated activity of the radiopharmaceutical present in a source region and a geometrical factor S. This approach, which a priori seems simple, in practice requires several SPECT/CT acquisitions, several measurements of the whole body activity and taking several blood samples, as well as hours of image processing and computation. The systematic implementation of these calculations, in all the patients we treat, will allow us to obtain homogeneous data to correlate the absorbed doses in the lesions with the biological effect of the treatment. The final purpose of the dosimetry calculations is to be able to maximize the therapeutic effect in the lesions, controlling the radiotoxicity in the organs at risk." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Implantar el cálculo dosimétrico en la práctica diaria de los servicios de Medicina Nuclear es, en estos momentos, un tema controvertido, en parte debido a la falta de una metodología estandarizada que sea aceptada por todas las partes interesadas (pacientes, médicos nucleares y radiofísicos). Sin embargo, desde la publicación del RD 601/2019 existe la obligación legal de ponerlo en marcha, a pesar de que es un procedimiento complejo y de alto consumo de recursos. El objetivo de este artículo es revisar las bases teóricas de la dosimetría in vivo en tratamientos con 177Lu-DOTATATE. La metodología expuesta es la propuesta por el Comité Medical Internal Radiation Dose (MIRD) de la Society of Nuclear Medicine & Molecular Imaging (SNMMI). Según este método, la dosis absorbida se obtiene como el producto de 2 factores: la actividad integrada en el tiempo de radiofármaco presente en una región fuente y un factor geométrico S. Esto, que a priori parece simple, en la práctica requiere de varias adquisiciones SPECT/CT, varias mediciones de cuerpo completo y de la obtención de varias muestras de sangre, así como de horas de procesado de imágenes y computación. La implantación sistemática del cálculo dosimétrico, en todos los pacientes que tratamos, permitirá obtener datos homogéneos para correlacionar las dosis absorbidas en las lesiones con el efecto biológico del tratamiento. El propósito final del cálculo dosimétrico es poder maximizar el efecto terapéutico en las lesiones, controlando la radiotoxicidad en los órganos de riesgo." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Montserrat Fuertes T, González García FM, Peinado Montes M.Á, Domínguez Grande ML, Martín Fernández N, Gómez de Iturriaga Piña A, et al. Descripción de la metodología para la cuantificación dosimétrica en tratamientos con 177Lu-DOTATATE. Rev Esp Med Nucl Imagen Mol. 2021;40:167–178." ] ] "multimedia" => array:20 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 970 "Ancho" => 1500 "Tamanyo" => 54299 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0045" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Simplified scheme of 177Lu decay." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1223 "Ancho" => 1508 "Tamanyo" => 169111 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "The source regions are those which for physiological or pathological reasons accumulate activity of the radiopharmaceutical. The target regions are those for which the dose absorbed is of interest. The dose absorbed in a determined target region is due to the activity present in one or several source regions." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1112 "Ancho" => 2500 "Tamanyo" => 76752 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0055" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Partial volume effect. The upper row shows spheres of different diameters, and the bottom row shows the images of each sphere obtained with a gamma camera. A dispersion effect of the counts can be observed which makes the volume measured in the image greater than the real volume, and consequently, the concentration of activity measured appears to be less than the concentration of real activity. This effect increases as the volume of the sphere diminishes. [Image taken from Physics in Nuclear Medicine, 4th Edition. Cherry, Sorenson and Phelps]." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 913 "Ancho" => 2500 "Tamanyo" => 152415 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0060" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "NEMA IEC Body Phantom with six spheres of different volumes (a) and transversal slice of the SPECT/CT image of the phantom (b)." ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1382 "Ancho" => 1500 "Tamanyo" => 117842 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0065" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Spectrum of 177Lu energy simulated with ME collimators. The solid line represents the total spectrum, while the dotted line represents the spectrum of the primary photons; that is, those which have not undergone any interaction in the phantom or in the collimator. It is observed that the photopeak of 208keV is that with the greater proportion of primary photons. [Image from MIRD Pamphlet No.26]." ] ] 5 => array:8 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 792 "Ancho" => 2833 "Tamanyo" => 212288 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0070" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Scheme of the collimator of a gamma camera and representation of the four components of collimator-detector effect that degrade image resolution: the intrinsic component of the detector (1), the geometric component of the collimator (2), the dispersion of photons in the collimator (3) and septal penetration (4). In the image, h is the height of the collimator, d the aperture and t is the thickness of the septa." ] ] 6 => array:8 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 919 "Ancho" => 2500 "Tamanyo" => 137285 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0075" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Geometry of whole body activity measurement." ] ] 7 => array:6 [ "identificador" => "eq0005" "etiqueta" => "(1)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "D (rT,TD)=∑rSA˜(rS,TD)∙S(rT⟵rS)" "Fichero" => "STRIPIN_si3.jpeg" "Tamanyo" => 2643 "Alto" => 37 "Ancho" => 258 ] ] 8 => array:6 [ "identificador" => "eq0010" "etiqueta" => "(2)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => 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=> "(12)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "Drm=A˜rmSrm⟵rm+∑hA˜hSrm⟵h+ A˜rbSrm⟵rb" "Fichero" => "STRIPIN_si38.jpeg" "Tamanyo" => 301 "Alto" => 13 "Ancho" => 14 ] ] 19 => array:6 [ "identificador" => "eq0065" "etiqueta" => "(13)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "Srm⟵rb=Srm⟵wb∙mwb,phanmrb,pat∙mrm,phanmrm,pat-Srm⟵rm∙mrm,phanmrb,pat∙mrm,phanmrm,pat-∑hSrm⟵h∙mh,phanmrb,pat∙mrm,phanmrm,pat" "Fichero" => "STRIPIN_si41.jpeg" "Tamanyo" => 387 "Alto" => 17 "Ancho" => 21 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:94 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Radioactive iodine in the study of 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Description of the methodology for dosimetric quantification in treatments with 177Lu-DOTATATE

Descripción de la metodología para la cuantificación dosimétrica en tratamientos con 177Lu-DOTATATE

T. Monserrat Fuertesa,b,

Corresponding author

temonsfmpr@gmail.com

Corresponding author.

, F.M. González Garcíac, M.Á. Peinado Montesa, M.L. Domínguez Grandec, N. Martín Fernándezc, A. Gómez de Iturriaga Piñab,d, P. Mínguez Gabiñae

a Servicio de Radiofísica y Protección Radiológica, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain

b Departamento de Cirugía, Radiología y Medicina Física, UPV/EHU, Leioa, Bizkaia, Spain

c Servicio de Medicina Nuclear, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain

d Servicio de Oncología Radioterápica, Hospital Universitario Gurutzeta-Cruces/Instituto de Investigación Sanitaria BioCruces, Barakaldo, Bizkaia, Spain

e Unidad de Protección Radiológica y Radiofísica, Hospital Universitario Gurutzeta-Cruces/Instituto de Investigación Sanitaria BioCruces, Barakaldo, Bizkaia, Spain

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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The source regions are those which for physiological or pathological reasons accumulate activity of the radiopharmaceutical&#46; The target regions are those for which the dose absorbed is of interest&#46; The dose absorbed in a determined target region is due to the activity present in one or several source regions&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Internal dosimetry in radiometabolic therapy &#40;RMT&#41; is not a novel concept since the first basic dosimetric calculations go back to the beginning of therapy for hyperthyroidism and thyroid cancer with iodine radioisotopes in the 1940s<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a>&#46; However&#44; its implementation in clinical practice is far from generalized as demonstrated in a European survey carried out in 2017<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this sense&#44; Spain is no exception&#44; despite the RD 1841&#47;1997 requiring estimation of the dose in &#8220;organs of special interest&#8221;&#59; that is&#44; to perform internal dosimetry&#46; This obligation was updated in the 2013&#47;59&#47;Euratom Directive and its transposition in RD 601&#47;2019&#44; which establishes that &#8220;<span class="elsevierStyleItalic">planning volumes be planned individually and be conveniently verified taking into account that the dose of healthy organs and tissues outside those considered in the planning should be as low as reasonably possible&#8221;</span>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">There is clearly an inexcusable legal obligation to perform internal dosimetry in all therapeutic procedures&#46; Nonetheless&#44; as in the rest of Europe&#44; internal dosimetry is not routinely performed in clinical practice in our country&#46; The main reason for this is the absence of clear evidence of the impact that internal dosimetry may have on the efficacy of treatment or the quality of life of the patients&#46; To this we must add the increase in the complexity of the procedures&#44; the human resources necessary and the length of equipment use as well as the inevitable need for collaboration with the Radiophysics Department&#46; In 2017&#44; the European Society of Nuclear Medicine &#40;EANM&#41; published a document that analyzed the feasibility of implementing treatment planning and verification procedures of the dose absorbed in the majority of treatments with RMT<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; This document highlights the inevitable increase in resources required for systematic performance of internal dosimetry&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">To implement routine internal dosimetry it is necessary to provide clear evidence of the global benefits that our patients would obtain and that this compensates for the unavoidable increase in complexity and cost associated with this implementation&#46; Nevertheless&#44; to obtain clear evidence of this hypothetical benefit it is necessary to perform exhaustive studies of dose-effect relationships for which dosimetry must be performed&#46; In addition&#44; in order to provide dosimetric results that are reproducible and comparable among different centers&#44; it is necessary to have standardized procedures with consensus by the different specialists and scientific societies involved&#46; This would facilitate the practical performance of the calculations and diminish the uncertainties&#46; With respect to these points&#44; in the 2014 review by Strigari et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> evidence of a dose-effect correlation was found in a large part of the RMT treatments analyzed&#46; Ideally&#44; individualization of the activities to administer to each patient would allow increasing the dose absorbed in the tumors&#44; and thereby increase the probability of therapeutic success while&#44; at the same time&#44; maintaining the dose in the organs at risk below the limits of toxicity<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The objective of this work is to summarize the basic concepts of internal dosimetry and describe&#44; step by step&#44; its practical application in the treatment of neuroendocrine tumors with <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#44; according to our experience&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Internal dosimetry&#58; MIRD method</span><p id="par0030" class="elsevierStylePara elsevierViewall">The methodology most widely used for performing internal dosimetry calculations in RMT treatments is that proposed by the Medical Internal Radiation Dose &#40;MIRD&#41; Committee of the Society of Nuclear Medicine &#38; Molecular Imaging &#40;SNMMI&#41;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a>&#46; According to the MIRD method&#44; the mean dose absorbed in a target region &#40;rT&#41; due to the activity of the radiopharmaceutical present in different source regions &#40;rS&#41; is calculated using the following formula&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><p id="par0035" class="elsevierStylePara elsevierViewall">The term A&#732;&#40;rS&#44;TD&#41; is the activity in the source region integrated over time&#59; that is&#44; it is the total number of decays produced in this region in the interval of temporal integration&#44; TD&#46; This interval covers the period of time from the point of radiopharmaceutical administration to the time this has completely disappeared from the source&#46; Factor A&#732;&#40;rS&#44;TD&#41; accounts for the temporal dependence of the problem&#59; that is&#44; the fact that the activity present in each source region changes over time&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The term S&#40;rT&#10229;rS&#41; is the dose absorbed in the target region by unit of activity integrated over time in the source region&#46; The S factors describe the physics of the transportation of radiation from the source region to the target region&#59; that is&#44; it accounts for the geometry of the problem&#46; These are calculated using Monte Carlo methods and are tabulated for different energies<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a>&#46; The summation of Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0005">&#40;1&#41;</a> allows several source regions to be included&#44; the activity of which contributes to the dose absorbed in a determined target region&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Based on what scale the source and target regions have been defined&#44; we refer to dosimetry at the organ level&#44; the voxel level or even to smaller scales<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#46; For example&#44; in dosimetry at a voxel level&#44; the source and target regions do not refer to organs but rather to voxels of the 3D image of the patient&#46; The corresponding S factors are different in each case&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Since the methodology of calculation at smaller scales is conceptually the same as at the organ level&#44; this article describes the calculation methodology of the mean dose at the organ or tumor level because it is currently the most frequently used&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Activity integrated over time</span><p id="par0055" class="elsevierStylePara elsevierViewall">To obtain the time-activity curve&#44; the activity of each source region of the patient must be sampled&#59; that is&#44; measured at various times after administration&#46; Depending on the case&#44; the activity is measured by images in a gamma camera or a positron emission tomography&#47;computerized tomography &#40;PET&#47;CT&#41; scan using an external probe or taking a blood sample&#46; The number of measurements and their temporal distribution should be chosen so that the adjustment curves reliably represents the real curve<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; The objective is to reproduce the real curve with the minimum number of measures possible to thereby limit the work load&#44; the time of use of the gamma cameras and discomfort to the patient&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A&#732;&#40;rS&#44;TD&#41; is calculated from the time-activity graph as the area under the curve for a temporal interval TD&#46; It can be determined by numerical integration or by analytical methods&#44; after previously adjusting the data to a mathematical function<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040"><span class="elsevierStyleItalic">S</span> factors at the organ level</span><p id="par0065" class="elsevierStylePara elsevierViewall">The S factors at the organ level are calculated by Monte Carlo methods in standard anthropomorphic phantoms<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13&#44;19&#44;20</span></a>&#46; The S factors are tabulated and represent the dose absorbed in each target organ per unit of activity integrated over time in any other source organ of the phantom&#46; In general&#44; the greatest contribution to the dose absorbed in each organ presenting uptake is that due to the activity present in the organ itself &#40;self-dose&#41;&#59; in many cases&#44; the dose due to the activity in other organs &#40;cross-dose&#41; can be obviated&#46; In the case of tumors or metastasis that are not included in the standard phantoms&#44; there are S factors tabulated for spherical masses of different volumes&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The main limitation inherent to the MIRD methodology at the organ level is that it makes two suppositions&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0075" class="elsevierStylePara elsevierViewall">It assumes that the distribution of activity&#44; and thus&#44; the dose absorbed&#44; is homogeneous in each organ&#59; that is&#44; it only allows calculating the average dose in each organ&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0080" class="elsevierStylePara elsevierViewall">It assumes that the geometry &#40;the shape and relative positive of the organs&#41; of the patient is identical to that of the standard phantom and&#44; moreover&#44; invariable along the treatment<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p></li></ul></p><p id="par0085" class="elsevierStylePara elsevierViewall">To overcome the limitation of these approaches&#44; methods that calculate the dose absorbed at the voxel level &#40;S-voxel factors and Monte Carlo calculations&#41; over the image of each individual patient have been proposed<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a>&#46; Although <span class="elsevierStyleItalic">a priori</span> these methods are more accurate&#44; they are more computationally costly and do not always provide more accurate results&#44; since in many cases the uncertainty is conditioned by the limited spatial resolution of the images<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE</span><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">177</span>Lu decays via &#946;<span class="elsevierStyleSup">&#8722;</span> to the fundamental state and to the three excited states of <span class="elsevierStyleSup">177</span>Hf&#44; with a half-life of 6&#46;647<span class="elsevierStyleHsp" style=""></span>d<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46; The &#946;<span class="elsevierStyleSup">&#8722;</span> emissions deposit their energy locally and can be considered the main contribution to the therapeutic effect&#46; The most abundant &#946;<span class="elsevierStyleSup">&#8722;</span> emission has a maximum kinetic energy of 498<span class="elsevierStyleHsp" style=""></span>keV &#40;probability 79 &#37;&#41;&#44; while the mean kinetic energy of all the &#946;<span class="elsevierStyleSup">&#8722;</span> particles emitted is 134<span class="elsevierStyleHsp" style=""></span>keV&#46; The maximum and mean ranges for &#946;<span class="elsevierStyleSup">&#8722;</span> emissions in soft tissue are 1&#46;7<span class="elsevierStyleHsp" style=""></span>mm and 0&#46;23<span class="elsevierStyleHsp" style=""></span>mm&#44; respectively<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#46; In turn&#44; by decaying at lower energy levels&#44; the photons emitted by <span class="elsevierStyleSup">177</span>Hf allow dosimetry based on images&#46; The principal photopeaks of the spectrum of <span class="elsevierStyleSup">177</span>Lu are found at 113<span class="elsevierStyleHsp" style=""></span>keV and 208<span class="elsevierStyleHsp" style=""></span>keV &#40;6&#46;20 and 10&#46;38 photons per 100 decays&#44; respectively<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows a simplified scheme of <span class="elsevierStyleSup">177</span>Lu decay&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">177</span>Lu-DOTATATE is a radiolabeled analog of somatostatin used in the treatment of patients with neuroendocrine tumors that are positive for receptors of this hormone&#46; In 2005&#44; the results of the first large clinical study on <span class="elsevierStyleSup">177</span>Lu-DOTATATE were published&#46; The radioisotope was administered in fractionated form almost always in 4 cycles of 7&#46;4<span class="elsevierStyleHsp" style=""></span>GBq each&#44; with 6&#8211;10 weeks between cycles<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46; No dose toxicity threshold was observed&#44; and this fractionation scheme has been adopted since then&#44; being considered as both safe and effective&#46; This is currently the administration protocol recommended by the Spanish Agency of Medication and Health Care Products &#40;AEMPS&#41;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>&#46; The phase III NETTER-1 trial evaluated the safety and efficacy of <span class="elsevierStyleSup">177</span>Lu-DOTATATE in the treatment of neuroendocrine tumors of metastatic midgut intestine<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#46; The trial demonstrated that the use of this radiopharmaceutical increased progression-free time and overall survival compared with unlabeled somatostatin and resulted in the registry of the radiopharmaceutical known today in the market as Lutathera&#174;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Dosimetry in treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE</span><p id="par0100" class="elsevierStylePara elsevierViewall">Planning dosimetry can be done in RMT after injecting a tracing activity of the radiopharmaceutical &#40;pretreatment planning&#41; or during the treatment after administering the therapeutic activity of the radiopharmaceutical &#40;peritreatment dosimetry&#41;&#46; In pretreatment dosimetry&#44; the activity needed to obtain a target dose absorbed is calculated<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a>&#46; In peritreatment dosimetry&#44; the dose absorbed in determined volumes of interest &#40;VOI&#41; after the administration is calculated&#46; In treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE the VOI are the primary tumor&#44; if it can be identified&#44; and the metastases&#44; which are mainly hepatic&#44; as well as the kidneys and bone marrow<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a> are the organs at risk&#46; In treatments fractionated in several cycles&#44; the peritreatment dosimetry of the first cycle can also be used to calculate the activity to administer to achieve a target dose in the later cycles&#46; Given the fixed administration schedule established by AEMPS for <span class="elsevierStyleSup">177</span>Lu-DOTATATE &#40;4 cycles of 7&#46;4<span class="elsevierStyleHsp" style=""></span>GBq&#41;&#44; the dosimetric procedures with this radioisotope are limited to peritreatment dosimetry without the possibility of varying the activity in posterior cycles to the first&#46; Nonetheless&#44; in clinical trials dosimetry has been used in the first treatment cycles to predict the dose in the following cycles and&#44; thus&#44; calculate the maximum number of cycles of 7&#46;4<span class="elsevierStyleHsp" style=""></span>GBq that can be given to a determined patient before achieving the dose of toxicity in the organs at risk<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The methodology for the calculation of the dose absorbed in <span class="elsevierStyleSup">177</span>Lu-DOTATATE is described below&#44; divided into three sections&#46; First&#44; the method to measure the activity is each of the source regions &#40;<span class="elsevierStyleItalic">quantification of activity</span>&#41; is described&#46; Secondly&#44; the number of times and at what time this activity is measured in each source region is specified as well as how to obtain the time-activity curve from which the activity integrated over time is calculated &#40;<span class="elsevierStyleItalic">sampling of the activity and calculation of the time-activity curve</span>&#41;&#46; Lastly&#44; once the activity integrated over time in each source region and the S factors are known&#44; the tables are taken and the dose absorbed in each target region is calculated &#40;<span class="elsevierStyleItalic">calculation of dose absorbed</span>&#41;&#46; Note that the source and target regions do not have to coincide&#58; there are source regions which uptake activity in which&#44; however&#44; it is of no interest to know the dose absorbed &#40;see <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The source regions in these treatments are the tumors and the metastases &#40;lesions&#41; as well as the kidneys&#44; spleen&#44; and bone marrow&#46; In addition&#44; the component of the rest of the body is also considered the source region which includes the whole body&#44; excluding these organs&#46; The target regions are the previously mentioned VOI&#59; that is&#44; the lesions and organs at risk &#40;kidneys and bone marrow&#41;&#46; Both the target regions and the organs at risk should be defined by the nuclear medicine physician before each treatment&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Quantification of activity</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Quantification of activity in solid organs and lesions based on SPECT&#47;CT images</span><p id="par0110" class="elsevierStylePara elsevierViewall">The emission of photons of <span class="elsevierStyleSup">177</span>Lu allows measuring the activity present in different zones of the body from images taken with a gamma camera&#46; In principle&#44; planar or tomographic images &#40;SPECT&#47;CT&#41; can be used or a hybrid methodology can be applied in which several planar images are acquired to obtain a relative time-activity curve and a SPECT&#47;CT image to normalize this curve<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;40</span></a>&#46; In general&#44; the choice of one modality or another depends on the means available in each installation&#46; Nevertheless&#44; in treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE the preferred method for dosimetry in both the kidneys<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> and in tumors or metastases is only based on SPECT&#47;CT images&#44; because it provides more exact quantification<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;42&#44;43</span></a> and is not limited by the overlapping of tissues inherent to planar acquisitions&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Characterization of the gamma camera</span><p id="par0115" class="elsevierStylePara elsevierViewall">To be able to quantify the activity of the radioisotope with SPECT&#47;CT images&#44; previous characterization of the gamma camera is necessary&#46; Firstly&#44; the calibration factor &#40;Fcal&#41; must be obtained to convert the count rate measured into activity&#46; In addition&#44; the recovery factors must be determined to correct the partial volume effect &#40;PVE&#41; and&#44; lastly&#44; characterize the dead time of the gamma camera&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Calibration factor</span><p id="par0120" class="elsevierStylePara elsevierViewall">Calibration of the gamma camera consists in obtaining the count rate detected per unit of activity of the radioactive source&#59; that is&#44; calculate its sensitivity&#46; The calibration factor Fcal is usually measured in counts per second per MBq &#40;cps&#47;MBq&#41;&#44; and to obtain this an image of a phantom with known activity must be acquired&#44; preferably in the same conditions of acquisition and reconstruction as that used in clinical practice&#46; There are different options when choosing the geometry of the calibration phantom&#46; The most common are&#58; point source&#44; Petri dish and cylindrical source<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#8211;50</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">To obtain a calibration factor for SPECT&#47;CT images D&#8217;Arienzo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> compared 4 different geometries&#58; a point source in air&#44; a 16<span class="elsevierStyleHsp" style=""></span>ml sphere in air&#44; a 16<span class="elsevierStyleHsp" style=""></span>ml sphere in water and a cylinder&#46; They obtained slightly worse results for the point source&#44; but the errors in quantification were less than 10&#37; of all the cases&#46; In turn&#44; Mezzenga et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> compared a 16<span class="elsevierStyleHsp" style=""></span>ml sphere in water with a cylinder phantom and concluded that cylindrical geometry may be the best option because it minimizes the PVE in the calibration acquisitions&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Partial volume effect</span><p id="par0130" class="elsevierStylePara elsevierViewall">The PVE is defined as the apparent reduction of the concentration of activity in a region of uptake due to the limited spatial resolution of the image system<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#46; This effect mainly appears as a consequence of the detector-collimator effect &#40;explained in the section on Image processing and analysis&#41;&#44; although it is also due to the structure of the voxels used to represent the images not coinciding with shape of the organs and the structures visualized&#46; With this&#44; the voxels of the borders between regions have a value of intermediate activity between the activities of the two adjacent regions&#44; creating a twilight effect in the image<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#46; The PVE affects both the activity measured in a VOI and its volume&#46; It depends on the characteristics of the imaging system&#44; the distribution of activity and the shape and volume of the VOI<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; the smaller the volume of the VOI the more evident the PVE&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">To correct this effect the usual method consists in using a phantom of spheres of different volumes in which a known concentration of <span class="elsevierStyleSup">177</span>Lu activity has been injected Areal&#46; Afterwards&#44; SPECT&#47;CT images of the phantom are obtained from which the concentration of activity measured in each sphere is obtained Ameasured&#46; To determine Ameasured in each sphere&#44; the surface delimiting the fluid with the activity of <span class="elsevierStyleSup">177</span>Lu is delineated slice by slice over the CT image&#46; Ideally&#44; the volume delimited by this surface should coincide with the real volume of fluid injected into each sphere&#46; The count rate corresponding to the fluid in each sphere is obtained from the SPECT image&#44; and by dividing the count rate by the calibration factor Fcal you obtain the mean activity&#46; The Ameasured concentration is determined as the ratio between this activity measured and the volume calculated in the CT image&#46; Finally&#44; the recovery coefficient &#40;RC&#41;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;43&#44;51&#8211;53</span></a> is obtained and is defined as the relation between the concentration of activity measured Ameasured and the concentration of real activity Areal&#58;<elsevierMultimedia ident="eq0010"></elsevierMultimedia></p><p id="par0140" class="elsevierStylePara elsevierViewall">The &#8239;RC can be obtained for any VOI in the patients by representing the RC values based on the volumes &#40;or the diameter&#41; of the spheres and adjusting the point obtained to a curve<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;54</span></a>&#46; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> shows a phantom of spheres for calculating the <span class="elsevierStyleItalic">RC</span>&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Dead time</span><p id="par0145" class="elsevierStylePara elsevierViewall">Ideally&#44; the count rate detected by the gamma camera is proportional to the activity&#44; maintaining the sensitivity &#40;cps&#47;MBq&#41; of the system constant&#46; However&#44; the gamma camera acts as a paralyzable system<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and for elevated count rates some events can be lost because the detector needs time &#40;short&#44; but not null&#41; to process each event detected during which it cannot detect another count&#46; Therefore&#44; for high activities a reduction in sensitivity is observed due to the dead time of the gamma camera&#46; This effect is especially important for isotopes that have many photon emissions&#44; such as <span class="elsevierStyleSup">131</span>I&#44; or in early acquisitions since&#44; in these cases&#44; the count rates are higher&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Given the characteristics of <span class="elsevierStyleSup">177</span>Lu emission<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#44; it is very unlikely for saturation effects of the detector of the gamma camera and loss of counts due to dead time to be produced in the clinical acquisitions except for acquisitions made during the first hours after administration&#46; Therefore&#44; it is not necessary to apply correction for dead time in acquisitions made the day after administration<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46; Nonetheless&#44; some authors have measured losses by dead time in the first clinical acquisition in some patients treated with <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#44; and have proposed different methods for correcting for this effect<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#8211;58</span></a>&#46; Losses by dead time in these studies were modest and were due to the first acquisition being made within the first 4<span class="elsevierStyleHsp" style=""></span>h after administration when the count rates were elevated&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Acquisition of images</span><p id="par0155" class="elsevierStylePara elsevierViewall">To quantify the activity of <span class="elsevierStyleSup">177</span>Lu with SPECT images&#44; the MIRD committee recommends acquiring an energy window of 15&#37;&#8211;20&#37; centered on the photopeak of 208<span class="elsevierStyleHsp" style=""></span>keV and with collimators of mean energy &#40;ME&#41;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46; The combination of ME collimators with the photopeak of 208<span class="elsevierStyleHsp" style=""></span>keV presents a greater relation of primary photons versus scattered photons&#59; that is&#44; less contribution of scattered radiation &#40;see <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41; and&#44; thus&#44; greater contrast in the images<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46; In general&#44; it is recommended to use matrices of 128<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>128&#44; but a matrix of 64<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>64 could be used for low count rates<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; With regard to the number of projections&#44; a range of projections of between 60 and 120 has been used in clinical studies with SPECT images<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46; The projection time may vary based on the count rate&#44; which&#44; in turn&#44; depends on the percentage of uptake and the time after administration&#46; Nonetheless&#44; to minimize patient discomfort and thereby reduce movement artefacts&#44; it is recommended to limit the total time of the SPECT acquisition to 30<span class="elsevierStyleHsp" style=""></span>minutes<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; This implies that the time per projection should be less according to an increase in the number of projections&#46; Finally&#44; the use of orbits with self-contouring is recommended so that the collimators can be as close as possible to the patient and thereby obtain the best spatial resolution possible<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">The recommended number of acquisitions is described in the section on <span class="elsevierStyleItalic">Sampling of the activity and calculation of the time-activity curve</span>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Image processing and analysis</span><p id="par0165" class="elsevierStylePara elsevierViewall">When reconstructing the SPECT image a series of factors which degrade the image and reduce the accuracy of the quantification of activity must be corrected&#46; An iterative method is recommended to perform the reconstruction&#44; because it allows correcting some of the effects which degrade the image in the process<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;55</span></a>&#46; The optimal number of iterations and subsets to use depends on the gamma camera&#46; The selection of the optimum value of these parameters should be determined during the characterization of the equipment by comparison of the images of the phantoms acquired with different technical conditions<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; The introduction of a filter in the reconstruction process can reduce the noise and improve the quality of the image&#44; but it can also affect the quantification and&#44; thus&#44; it is not always recommendable in dosimetry acquisitions&#46; It must be ensured that the filtrate does not affect the accuracy of the quantification<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;55</span></a>&#46; The same acquisition may be valid for the medical diagnosis and for dosimetry&#44; using the appropriate parameters of reconstruction in each case&#46; Below&#44; the principal effects which degrade the projections acquired are summarized&#46;</p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Attenuation</span><p id="par0170" class="elsevierStylePara elsevierViewall">The flow of photons of 208<span class="elsevierStyleHsp" style=""></span>keV is reduced to half with a soft tissue thickness of 5<span class="elsevierStyleHsp" style=""></span>cm&#59; that is&#44; the attenuation in the patient has an important effect on the number of photons that reach the gamma camera<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46; The grade of attenuation depends on the position from which the photons are emitted and the different densities of tissue through which they pass inside the patient&#46; It is therefore important to obtain a specific attenuation map for each patient<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; There are several methods to obtain this map&#44; the most accurate being that which uses the information of the CT image of the SPECT&#47;CT equipment&#46; After obtaining the map and correcting for the attenuation corresponding to the energy of <span class="elsevierStyleSup">177</span>Lu&#44; the number of counts of each voxel of the SPECT image is corrected by attenuation&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Scattered radiation</span><p id="par0175" class="elsevierStylePara elsevierViewall">Scattered radiation is formed by secondary photons which are detected in the photopeak window after having undergone one or more scattering events in the tissue and&#47;or the collimator&#44; and which&#44; thus&#44; generate counts in positions and energies different from those of the original photon&#46; The proportion of scattered photons detected in the acquisition window mainly depends on the width of the window of the photopeak&#44; the energy of the photons&#44; the distance they travel within the patient and the coefficient of attenuation of the tissue they pass through &#40;air&#44; bone&#8230;&#41;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#46; In the acquisition of <span class="elsevierStyleSup">177</span>Lu with the ME collimator&#44; this proportion is of around 20&#37;&#8211;30&#37; of the total photons that reach the detector<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">To correct for the effect of scattered radiation&#44; the method most used is the triple energy window &#40;TEW&#41; method<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&#44; which uses the counts acquired in the two windows of the spectrum at both sides of the photopeak and estimates the component of scattered radiation in the photopeak making a trapezoidal approach&#46; A variation is the double energy window &#40;DEW&#41; method<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&#44; which uses a single scatter radiation window to the left of the photopeak and is applied in cases in which the component of scattered radiation in the upper window is null or very low<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#46; This is the case of <span class="elsevierStyleSup">177</span>Lu when ME collimators are used<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;62</span></a>&#44; provided that the count rates are not excessively high<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;58</span></a>&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Collimator-detector response</span><p id="par0185" class="elsevierStylePara elsevierViewall">Collimator-detector response makes the image of a specific object appear blurry&#44; affecting not only the quality of the image but also the accuracy of the quantification of activity&#46; Its importance increases with the distance to the collimator<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#46; Collimator-detector response is made up of four components&#46; The first is associated with the intrinsic response of the detector which has a certain spatial resolution&#46; The second is the geometric component of the collimator&#58; although the holes of the collimators of the gamma cameras are narrow&#44; it is possible for photons that arrive with a certain angle of incidence to pass through and reach the detector&#46; This increases the uncertainty of the positioning of the radioactive events that generated those photons&#46; The third component is due to the scattering events mainly occurring in the collimator&#46; Finally&#44; the fourth component is due to the possibility that some very energetic photons penetrate the septa of the collimators &#40;component of septal penetration&#41;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; Each of these four components is shown in <a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#46; To correct for the intrinsic response of the detector and the geometric component of the collimator&#44; the point spread function &#40;PSF&#41; is used in the reconstruction process<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&#46; The correction of the scatter component in the collimator is included in the method of scattering correction mentioned in the previous section&#46; Finally&#44; Monte Carlo simulations can be performed or modified PSFs can be applied to correct the septal penetration<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Activity in each VOI</span><p id="par0190" class="elsevierStylePara elsevierViewall">The activity present in each region of interest of the image is quantified by the count rates in this zone&#44; applying the pertinent corrections as in the following equation&#58;<elsevierMultimedia ident="eq0015"></elsevierMultimedia></p><p id="par0195" class="elsevierStylePara elsevierViewall">CVOI is the count rate measured in VOI corrected during the reconstruction for the effects of attenuation&#44; disperse radiation and collimator-detector&#46; To correct these three effects&#44; the methods most commonly used are&#44; respectively&#44; the CT attenuation map&#44; the TEW method and the PSF&#46; Fcal is the calibration factor&#44; RC is the recovery coefficient corresponding to the volume of the VOI and DTF is the correction factor for dead time in each VOI&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">As explained previously&#44; correction for dead time is not necessary for images of <span class="elsevierStyleSup">177</span>Lu acquired after the day following the administration of the radiopharmaceutical&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Quantification of activity in bone marrow</span><p id="par0205" class="elsevierStylePara elsevierViewall">In RMT treatments the dose absorbed in bone marrow is considered to have three components&#58; that due to the activity present in the bone marrow itself&#44; that due to the activity present in other organs with physiological uptake and that due to the activity present in the rest of the body<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#46; In treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#44; the contribution to the dose absorbed due to the activity present in the organs with greatest physiological uptake and in the rest of the body is estimated at between 15&#37; and 68&#37;&#44; and should not be disregarded<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;66&#44;67</span></a>&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">To determine the activity present in the bone marrow itself the concentration of activity in blood is measured&#46; The most common method to do this is with a duly calibrated gamma counter &#40;well type&#41; of NaI &#40;T1&#41; &#40;although a beta counter or a semiconductor detector can also be used<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#41;&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">To quantify activity in the rest of the body the activity in the whole body is measured and then the contributions of the bone marrow and the organs with physiological uptake obtained in SPECT&#47;CT images are subtracted&#46;</p><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Characterization of the equipment</span><p id="par0220" class="elsevierStylePara elsevierViewall">The response of the well counter in which the blood samples of the patients are measured should be well characterized&#44; and this means that the calibration factor for the energy of <span class="elsevierStyleSup">177</span>Lu must be known and the appropriate corrections for dead time and geometry must be applied<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a>&#46; To obtain a calibration factor&#44; a certain volume can be extracted from a source of calibrated <span class="elsevierStyleSup">177</span>Lu <a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;68</span></a> &#40;e&#46;g&#46; that used for the calibration of the activimeter&#41;&#46; The activity extracted is measured in the activimeter and is used to prepare an aqueous solution of <span class="elsevierStyleSup">177</span>Lu&#44; from which an aliquot is extracted to obtain the calibration factor of the counter&#46; The use of a precision balance can help to achieve greater accuracy in the value of weight and&#44; thus&#44; of the concentration of the solution&#46; The activity of the aliquot extracted from the solution should be sufficiently low to be able to avoid losses by dead time in the well counter&#46; In addition&#44; to eliminate the need for geometric corrections&#44; the aliquot can be prepared with the same geometry &#40;identical recipient&#44; same volume&#41; with which the patient blood samples are prepared&#46; The calibration factor of the well counter is the count rate measured divided by the activity of the aliquot&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Acquisition of measurements</span><p id="par0225" class="elsevierStylePara elsevierViewall">The measurement of the concentration of activity in blood is made in volumes of 1 or 2<span class="elsevierStyleHsp" style=""></span>ml&#44; obtained from the blood samples of the patient extracted from the contralateral arm of the administration of the radiopharmaceutical to avoid contamination&#46; The number of samples recommended is described in the section on <span class="elsevierStyleItalic">Sampling of activity and calculation of the time-activity curve</span>&#46; It is recommended to measure all the samples on the same day and apply the corresponding correction for the physical decay of <span class="elsevierStyleSup">177</span>Lu&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Activity in bone marrow</span><p id="par0230" class="elsevierStylePara elsevierViewall">When there is no specific uptake of activity in the bone marrow cells as in the case of treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>&#44; it is assumed that the concentration of activity in bone marrow Arm is proportional to the concentration of activity in blood &#8239;Abl<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a>&#58;<elsevierMultimedia ident="eq0020"></elsevierMultimedia>where the constant RMBLR &#40;red marrow to blood level ratio&#41; is the ratio of concentrations of activity in bone marrow and in blood&#46; In radioimmunotherapy RMBLR values have been obtained with different isotopes ranging from 0&#46;2 up to 0&#46;4<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;70</span></a>&#46; In regard to treatments with somatostatin peptide analogs&#44; Forrer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> performed bone marrow aspirates together with blood extractions in a total of 15 patients treated with &#91;<span class="elsevierStyleSup">177</span>Lu-DOTA0&#44;Tyr3&#93;octreotate&#44; and obtained a <span class="elsevierStyleItalic">RMBLR</span> value &#8773;1&#59; that is&#44; they concluded that the concentration of activity present in the red marrow is equal to the concentration of activity present in blood&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Using Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0020">&#40;4&#41;</a> and a <span class="elsevierStyleItalic">RMBLR</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; the following Formula <a class="elsevierStyleCrossRef" href="#eq0025">&#40;5&#41;</a> for activity in bone marrow is obtained&#58;<elsevierMultimedia ident="eq0025"></elsevierMultimedia>where mrm&#44;pat is the mass of the bone marrow of the patient that is calculated by linearly scaling the mass of the bone marrow of the standard phantom mrm&#44;phan by the mass of the whole body of the patient mwb&#44;pat and the phantom mwb&#44;phan&#59; that is&#44; applying a rule of three as shown in Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0030">&#40;6&#41;</a><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>&#46; The masses of the phantom are tabulated in ICRP 110<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46;<elsevierMultimedia ident="eq0030"></elsevierMultimedia></p><p id="par0240" class="elsevierStylePara elsevierViewall">Therefore&#44; to quantify Arm blood samples are taken from the patient and the concentration of activity is measured in the well counter&#46; In addition to this method&#44; based on measuring activity concentrations in blood&#44; there are proposals based on quantification with images<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">67&#44;72&#44;73</span></a>&#46; Quantifying the concentration of activity in bone marrow from images may be useful when the patient presents bone metastases with significant uptake&#44; given that in these cases the blood sample method would underestimate the dose absorbed in the bone marrow&#46;</p></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Quantification of whole body activity</span><p id="par0245" class="elsevierStylePara elsevierViewall">Whole body activity can be measured by the acquisition of a whole body scan in a gamma camera&#46; However&#44; a simpler practical option is to use an external probe which can be a gaseous detector &#40;ionization camera or Geiger&#8211;M&#252;ller&#41; or scintillation crystal<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; The option of the external probe has an important advantage and it is that the measures performed are much more rapid and do not require gamma camera time&#46; Thus&#44; more measures can be made and thus there are more points when adjusting the time-activity curve<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a>&#46;</p><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Characterization of the equipment</span><p id="par0250" class="elsevierStylePara elsevierViewall">The external probe used to measure whole body activity should be calibrated and certified by an accredited calibration laboratory and characterized for measuring count rates of the energy of the photons emitted by <span class="elsevierStyleSup">177</span>Lu and for the range of activities of the treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59&#44;74</span></a>&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Acquisition of the measures</span><p id="par0255" class="elsevierStylePara elsevierViewall">For whole body measurements&#44; the first acquisition with the external probe should always be made immediately after the administration and before the patients has excreted activity&#46; This allows the conversion factor to be obtained which relates the magnitude measured by the probe &#40;cps&#44; &#956;Sv&#47;h&#44; etc&#46;&#41; with the activity present in the body of the patient which is known in the first moment &#40;real activity administered&#44; calculated from the measurements of the full and empty vial in the activimeter&#41;&#46; The remaining acquisitions are always made after the patient has urinated so that the content of the bladder does not distort the results<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#46; The recommended number of measures is described in the section on <span class="elsevierStyleItalic">Sampling of the activity and calculation of the time-activity curve</span>&#46; Special care should be made to always reproduce the same geometry&#46; To minimize the effect that the attenuation of the patients themselves might have on the result of the acquisitions&#44; each acquisition should have two measures&#44; one anterior &#40;AP&#41; and anther posterior &#40;PA&#41;&#44; both with the probe at the same distance from the patient<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Whole body activity</span><p id="par0260" class="elsevierStylePara elsevierViewall">Whole body activity at each time t is the geometric measure of the two measures taken with the external probe &#40;AP and PA&#41;&#44; corrected by the conversion factor<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#58;<elsevierMultimedia ident="eq0035"></elsevierMultimedia>where A0 is the activity administered&#44; CAP&#44;t and CPA&#44;t are the anterior &#40;AP&#41; and posterior &#40;PA&#41; measures of the probe at the time t and CAP&#44;0 and CPA&#44;0 are the anterior &#40;AP&#41; and posterior &#40;PA&#41; measures of the probe at the time of administration &#40;t&#61;0&#41;&#46;</p></span></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Sampling of the activity and calculation of the time-activity curve</span><p id="par0265" class="elsevierStylePara elsevierViewall">To reduce the uncertainties in the adjustment of the data to a curve&#44; a minimum of three measures per each phase of the kinetics of the radiopharmaceutical is recommended<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;64&#44;73</span></a>&#46; The optimal times to perform the acquisitions depends on the effective elimination time of the radiopharmaceutical in each tissue &#40;Te&#41;&#46; It is generally recommended to make one or two acquisitions at some fraction of <span class="elsevierStyleItalic">T</span><span class="elsevierStyleInf">e</span>&#44; another around Te and another&#44; or two last acquisitions after 3&#8211;5 times <span class="elsevierStyleItalic">T</span><span class="elsevierStyleInf">e</span><a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; It is important to conveniently characterize the last retention phase which presents the greatest contribution to the activity integrated over time<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a>&#46; To obtain the activity integrated over time from the data obtained any integration method can be used &#40;trapezoidal method or analytical integration after adjusting the data to an exponential or sum of exponentials&#41;&#46;</p><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Solid organs and lesions</span><p id="par0270" class="elsevierStylePara elsevierViewall">Two phases can be identified in the kinetics of <span class="elsevierStyleSup">177</span>Lu-DOTATATE<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46; The first is rapid elimination from the blood and uptake in organs that lasts an average of 4<span class="elsevierStyleHsp" style=""></span>h<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#44; and the second is of slow elimination which may approximate a simple exponential<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; On having two phases&#44; in theory a minimum of six measures of the activity in organs should be made to correctly sample the time-activity curve<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; However&#44; since the uptake phase is very short&#44; the activity in the organs of interest changes very rapidly&#44; and the measures of activity can&#44; as a result&#44; give distorted data&#46; Therefore&#44; in practice it is acceptable to assume instantaneous uptake and sample only the elimination phase<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; To do this&#44; three SPECT&#47;CT acquisitions should be made&#46; Since the Te is not known <span class="elsevierStyleItalic">a priori</span> and&#44; in addition&#44; it is different for the different tissues&#44; the literature describes different sampling schemes&#46; For example&#44; Sandstr&#246;m et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and Garske et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> acquire images at 24&#44; 72 and 168<span class="elsevierStyleHsp" style=""></span>h post-administration&#46; Other groups<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#44;79&#44;80</span></a> acquire images at around 4&#44; 24 and 72<span class="elsevierStyleHsp" style=""></span>h post-administration&#46; Santoro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> propose four measurement points&#58; at 4&#44; 24&#44; 72 and 192<span class="elsevierStyleHsp" style=""></span>h&#46; Different attempts have been made to reduce the number of SPECT&#47;CT acquisitions necessary for the dosimetry to solid organs and lesions&#44; although most are limited to renal dosimetry<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;82&#8211;84</span></a>&#46; Freedman and cols<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> compared the results of doses to solid organs and lesions obtained at 4&#44; 3 and 2 sampling points&#46; They concluded that three SPECT&#47;CT &#40;at 24&#44; 72 and 168<span class="elsevierStyleHsp" style=""></span>h post-administration&#41; provide a good estimation of the dose absorbed&#46; The method based on two SPECT&#47;CT is also feasible&#44; although it would increase the uncertainty of the results&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Blood</span><p id="par0275" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">177</span>Lu-DOTATATE is intravenously administered and is rapidly eliminated from the blood&#44; counting its kinetics in two phases of elimination<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; Therefore&#44; for sampling the time-activity curve and following the recommendations of the EANM<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#44;75</span></a>&#44; at least six blood samples of the patients should be taken in the first 24<span class="elsevierStyleHsp" style=""></span>h&#44; and it would be recommendable to take at least one more in the delayed phase between 24<span class="elsevierStyleHsp" style=""></span>h and 168<span class="elsevierStyleHsp" style=""></span>h post-administration<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46;</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Whole body</span><p id="par0280" class="elsevierStylePara elsevierViewall">It has been observed that the kinetics of <span class="elsevierStyleSup">177</span>Lu-DOTATATE in the whole body can also be described by two phases of elimination&#44; a first rapid phase in the first 24<span class="elsevierStyleHsp" style=""></span>h and a second slower phase thereafter<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; Therefore&#44; at least 6 measures must be made during the first week after administration&#44; the 3 or 4 first measures within 24<span class="elsevierStyleHsp" style=""></span>h for conveniently sampling the two phases of elimination&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">After having obtained the activities integrated over time in the whole body&#44; bone marrow and in solid organs&#44; the activity integrated over time in the remainder of the body is calculated by the following Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0040">&#40;8&#41;</a>&#46;<elsevierMultimedia ident="eq0040"></elsevierMultimedia></p><p id="par0290" class="elsevierStylePara elsevierViewall">A&#732;rb is the activity integrated over time in the remainder of the body&#44; A&#732;wb is the activity integrated over time in the whole body&#44; A&#732;rm is the activity integrated over time in red marrow and A&#732;h is the activity integrated over time in the organ h with physiological uptake&#46;</p></span></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Calculation of the dose absorbed</span><p id="par0295" class="elsevierStylePara elsevierViewall">Once the activity integrated over time in the main VOI is known&#44; the dose absorbed is calculated by applying Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0005">&#40;1&#41;</a> of the MIRD method&#46; The S factors associated with the term of self-dose of an organ h &#40;in which &#946; emissions dominate&#41; are usually linearly scaled to the mass of the organ of the patient<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a>&#44; while the S factor associated with terms of cross-dose of an organ i to another organ h &#40;due to &#947; emissions&#41; is considered independent of the mass<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#44;87</span></a>&#46; Therefore&#58;<elsevierMultimedia ident="eq0045"></elsevierMultimedia>where mh&#44;phan and mh&#44;pat are the masses of organ h of the reference phantom and the organ h of the patient&#44; respectively&#46;</p><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Solid organs and lesions</span><p id="par0300" class="elsevierStylePara elsevierViewall">To calculate the dose absorbed in solid organs and lesions &#40;primary tumor or metastasis&#41; we must&#44; on one hand&#44; calculate the dose due to the activity present in the organ or lesion itself &#40;self-dose&#41; and the cross-dose&#44; on the other hand&#44; of any organ that accumulates radiotracer and the emission of which can reach the kidneys or the lesions&#46; Thus&#44; following the MIRD methodology&#44; the dose absorbed in kidneys and spleen is calculated with the following formulas<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#58;<elsevierMultimedia ident="eq0050"></elsevierMultimedia></p><p id="par0305" class="elsevierStylePara elsevierViewall">However&#44; as mentioned previously&#44; in most of the cases&#44; the principal contribution to the dose absorbed is that due to the activity in the organ itself&#44; and it can be reasonably assumed that the cross components are negligible &#40;the factors Skidneys&#10229;spleen and Sspleen&#10229;kidneys are three orders of magnitude inferior to the factors Sspleen&#10229;spleen and Skidneys&#10229;kidneys&#41;&#46; It should be taken into account that although the spleen is an organ with physiological uptake&#44; it is not usually considered an organ at risk in these treatments<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a>&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">To determine the dose absorbed in the lesion &#40;tumor or metastasis&#41;&#44; &#8239;Dlesion&#44; only the dose due to the activity present in the lesion itself &#40;self-dose&#41; is considered&#58;<elsevierMultimedia ident="eq0055"></elsevierMultimedia></p><p id="par0315" class="elsevierStylePara elsevierViewall">In this case Sspherical&#44;vol is the S factor corresponding to a sphere with a volume equal to that of the lesion&#44; interpolated from the tables obtained with Monte Carlo for the emmission energies of the radioisotope&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Bone marrow</span><p id="par0320" class="elsevierStylePara elsevierViewall">As explained previously&#44; the dose absorbed in the bone marrow has three components so that the general MIRD equation &#40;Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0005">&#40;1&#41;</a>&#41; remains as follows in this case&#58;<elsevierMultimedia ident="eq0060"></elsevierMultimedia></p><p id="par0325" class="elsevierStylePara elsevierViewall">The factors Srm&#10229;rm and Srm&#10229;h are tabulated for standard phantoms<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&#46; To calculate those corresponding to the patient they must be scaled according to Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0045">&#40;9&#41;</a>&#46; The factor Srm&#10229;rb is not tabulated since the component of the remainder of the body depends on what organs are to be treated and this is calculated with the following Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0065">&#40;13&#41;</a><a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#44;87</span></a>&#58;<elsevierMultimedia ident="eq0065"></elsevierMultimedia>where the subindices <span class="elsevierStyleItalic">rm</span>&#44; <span class="elsevierStyleItalic">wb</span>&#44; <span class="elsevierStyleItalic">rb</span> and <span class="elsevierStyleItalic">h</span> are red marrow&#44; whole body&#44; remainder of the body and &#8220;other organs&#8221;&#44; respectively&#44; and the subindices <span class="elsevierStyleItalic">phan</span> and <span class="elsevierStyleItalic">pat</span> refer to the phantom and patient&#44; respectively&#46; Direct measurement of the mass of the red marrow of the patient is not possible&#44; and it is therefore calculated from the mass of the red marrow of the standard phantom with Eq&#46; <a class="elsevierStyleCrossRef" href="#eq0030">&#40;6&#41;</a><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>&#46;</p></span></span></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Uncertainties in the calculations</span><p id="par0330" class="elsevierStylePara elsevierViewall">All the numerical calculations made from experimental data have an uncertainty associated&#44; and dosimetry calculations are no exception<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">89&#44;90</span></a>&#46; In 2011&#44; Lassmann et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> described the need to evaluate the uncertainties in the measures and the calculations of internal dosimetry as a fundamental part of the scientific analysis&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">In a complete internal dosimetry calculation there are many sources of uncertainty to consider&#44; and detailed quantification of all of these uncertainties is a laborious process&#46; To perform the calculation&#44; the uncertainties associated with the final dose can be divided into two groups&#58; those associated with the activity integrated over time and those that affect the geometric factors of the problem&#46; The uncertainties of the first group depend on the method used to measure the activity &#40;planar images&#44; SPECT&#47;CT&#44; external probe&#44; etc&#46;&#41; of the data sample performed &#40;the number of acquisitions and the time at which they were made&#41; and the method of integration&#46; The uncertainties of the second group depend on the dosimetric method used &#40;MIRD at an organ level&#44; MIRD at a voxel level&#44; Monte Carlo&#41;&#46; Obviously&#44; to evaluate the uncertainty of the final dose both groups should be considered&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">One would think that as the calculations are refined and the scales worked with are smaller and increasingly more based on the particular characteristics of each patient&#44; going from MIRD at an organ level to MIRD at a voxel level and afterwards to the Monte Carlo calculation&#44; the uncertainty in the absorbed dose would be increasingly less&#46; However&#44; due to the limited spatial resolution of the gamma cameras&#44; the uncertainties in the quantification of the activity may be greater than the uncertainty associated with the dosimetric method used&#44; especially in very small lesions<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a>&#44; making&#44; in some cases&#44; the investment in calculations more exact&#44; but computationally more costly&#44; unjustified<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a>&#46;</p><p id="par0345" class="elsevierStylePara elsevierViewall">In 2018&#44; the EANM published guidelines for the analysis of uncertainties in the calculations of RMT doses based on the MIRD method<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a>&#46; They analyze the multiplication of uncertainties along the whole dosimetric calculation chain until the mean dose absorbed in each VOI and its uncertainty are obtained&#46; The document presents an example of a patient who received <span class="elsevierStyleSup">90</span>Y-DOTATATE for treatment and <span class="elsevierStyleSup">111</span>In-DOTATATE for images&#46; It calculated the dose absorbed and the uncertainties in lesions&#44; kidneys&#44; liver and spleen and obtained uncertainty of around 35&#37; in the lesions&#44; being less in the remaining regions&#46; Following the methodology proposed by this guideline&#44; in 2020 Finocchiaro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> carried out an analysis of uncertainties in a total of 154 lesions from 49 patients receiving RMT&#46; They obtained a wide range of uncertainties &#40;14&#37;&#8211;102&#37;&#41; and identified the principal source as the uncertainty in the volume of each VOI&#44; associated with the delineation process&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">In the particular case of dosimetry to the kidneys in treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#44; Gustafsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> analyzed uncertainties in a virtual patient model&#46; With this model they identified the main sources of uncertainties as those associated with the calibration factor and the coefficients of recovery corrected by PVE&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">In the end&#44; the uncertainty in the calculation of internal dosimetry should appear in the dosimetry report&#44; and it is important to consider it when evaluating each dose result<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a>&#46;</p></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Conclusions</span><p id="par0360" class="elsevierStylePara elsevierViewall">Dosimetry in treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE is divided into dosimetry of lesions and dosimetry of organs at risk &#40;bone marrow and kidneys&#41;&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">Dosimetry requires previous characterization of the equipment for making the measurements&#58; gamma camera&#44; well counter and external probe&#46; Characterization of the gamma camera involves several acquisitions with different phantoms and requires a source of <span class="elsevierStyleSup">177</span>Lu with known activity&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">To make a complete dosimetry calculation at least three SPECT&#47;CT acquisitions are necessary as well as six blood extractions and 6 whole body measures of the patient during the first week after administration&#46; This represents an increase in the work load and patient discomfort&#46; However&#44; these procedures should be assumable by most services with RMT units&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">The methodology of dosimetric quantification described in the present article allows estimating the absorbed dose in <span class="elsevierStyleSup">177</span>Lu-DOTATATE treatments and&#44; thus&#44; fulfill the 2013&#47;59&#47;Euratom Directive&#46; Therefore&#44; it is possible and necessary to modify the protocols of routine work procedures of the therapeutic services of Nuclear Medicine to include dosimetry calculations which will improve both their efficacy and safety&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Conflict of interest</span><p id="par0380" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Implementation of dosimetry calculations in the daily practice of Nuclear Medicine Departments is&#44; at this time&#44; a controversial issue&#44; partly due to the lack of a standardized methodology that is accepted by all interested parties &#40;patients&#44; nuclear medicine physicians and medical physicists&#41;&#46; However&#44; since the publication of RD 601&#47;2019 there is a legal obligation to implement it&#44; despite the fact that it is a complex and high resource consumption procedure&#46; The aim of this article is to review the theoretical bases of in vivo dosimetry in treatments with <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#46; The exposed methodology is the one proposed by the MIRD Committee &#40;Medical Internal Radiation Dose&#41; of the SNMMI &#40;Society of Nuclear Medicine &#38; Molecular Imaging&#41;&#46; According to this method&#44; the absorbed dose is obtained as the product of 2 factors&#58; the time-integrated activity of the radiopharmaceutical present in a source region and a geometrical factor S&#46; This approach&#44; which a priori seems simple&#44; in practice requires several SPECT&#47;CT acquisitions&#44; several measurements of the whole body activity and taking several blood samples&#44; as well as hours of image processing and computation&#46; The systematic implementation of these calculations&#44; in all the patients we treat&#44; will allow us to obtain homogeneous data to correlate the absorbed doses in the lesions with the biological effect of the treatment&#46; The final purpose of the dosimetry calculations is to be able to maximize the therapeutic effect in the lesions&#44; controlling the radiotoxicity in the organs at risk&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Implantar el c&#225;lculo dosim&#233;trico en la pr&#225;ctica diaria de los servicios de Medicina Nuclear es&#44; en estos momentos&#44; un tema controvertido&#44; en parte debido a la falta de una metodolog&#237;a estandarizada que sea aceptada por todas las partes interesadas &#40;pacientes&#44; m&#233;dicos nucleares y radiof&#237;sicos&#41;&#46; Sin embargo&#44; desde la publicaci&#243;n del RD 601&#47;2019 existe la obligaci&#243;n legal de ponerlo en marcha&#44; a pesar de que es un procedimiento complejo y de alto consumo de recursos&#46; El objetivo de este art&#237;culo es revisar las bases te&#243;ricas de la dosimetr&#237;a in vivo en tratamientos con <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#46; La metodolog&#237;a expuesta es la propuesta por el Comit&#233; Medical Internal Radiation Dose &#40;MIRD&#41; de la Society of Nuclear Medicine &#38; Molecular Imaging &#40;SNMMI&#41;&#46; Seg&#250;n este m&#233;todo&#44; la dosis absorbida se obtiene como el producto de 2 factores&#58; la actividad integrada en el tiempo de radiof&#225;rmaco presente en una regi&#243;n fuente y un factor geom&#233;trico S&#46; Esto&#44; que a priori parece simple&#44; en la pr&#225;ctica requiere de varias adquisiciones SPECT&#47;CT&#44; varias mediciones de cuerpo completo y de la obtenci&#243;n de varias muestras de sangre&#44; as&#237; como de horas de procesado de im&#225;genes y computaci&#243;n&#46; La implantaci&#243;n sistem&#225;tica del c&#225;lculo dosim&#233;trico&#44; en todos los pacientes que tratamos&#44; permitir&#225; obtener datos homog&#233;neos para correlacionar las dosis absorbidas en las lesiones con el efecto biol&#243;gico del tratamiento&#46; El prop&#243;sito final del c&#225;lculo dosim&#233;trico es poder maximizar el efecto terap&#233;utico en las lesiones&#44; controlando la radiotoxicidad en los &#243;rganos de riesgo&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Montserrat Fuertes T&#44; Gonz&#225;lez Garc&#237;a FM&#44; Peinado Montes M&#46;&#193;&#44; Dom&#237;nguez Grande ML&#44; Mart&#237;n Fern&#225;ndez N&#44; G&#243;mez de Iturriaga Pi&#241;a A&#44; et al&#46; Descripci&#243;n de la metodolog&#237;a para la cuantificaci&#243;n dosim&#233;trica en tratamientos con <span class="elsevierStyleSup">177</span>Lu-DOTATATE&#46; Rev Esp Med Nucl Imagen Mol&#46; 2021&#59;40&#58;167&#8211;178&#46;</p>"
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