Radiopharmacokinetic modelling and radiation dose assessment of 223Ra used for treatment of metastatic castration-resistant prostate cancer.

PURPOSE: Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study. METHODS: The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, [Formula: see text] in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned [Formula: see text] values. RESULTS: The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon. CONCLUSION: The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

Organ doses of the fetus from external environmental exposures.

This article presents nuclide-specific organ dose rate coefficients for environmental external exposures due to soil contamination assumed as a planar source at a depth of 0.5 g cm-2 in the soil and submersion to contaminated air, for a pregnant female and its fetus at the 24th week of gestation. Furthermore, air kerma free-in-air coefficient rates are listed. The coefficients relate the organ equivalent dose rates (Sv s-1) to the activity concentration of environmental sources, in Bq m-2 or Bq m-3, allowing to time-integrate over a particular exposure period. The environmental radiation fields were simulated with the Monte Carlo radiation transport codes PHITS and YURI. Monoenergetic organ dose rate coefficients were calculated employing the Monte Carlo code EGSnrc simulating the photon transport in the voxel phantom of a pregnant female and fetus. Photons of initial energies of 0.015-10 MeV were considered including bremsstrahlung. By folding the monoenergetic dose coefficients with the nuclide decay data, nuclide-specific organ doses were obtained. The results of this work can be employed for estimating the doses from external exposures to pregnant women and their fetus, until more precise data are available which include coefficients obtained for phantoms at different stages of pregnancy.

Uncertainty analysis in internal dose calculations for cerium considering the uncertainties of biokinetic parameters and S values.

Radioactive cerium and other lanthanides can be transported through the aquatic system into foodstuffs and then be incorporated by humans. Information on the uncertainty of reported dose coefficients for exposed members of the public is then needed for risk analysis. In this study, uncertainties of dose coefficients due to the ingestion of the radionuclides 141Ce and 144Ce were estimated. According to the schema of internal dose calculation, a general statistical method based on the propagation of uncertainty was developed. The method takes into account the uncertainties contributed by the biokinetic models and by the so-called S values. These S-values were derived by using Monte Carlo radiation transport simulations with five adult non-reference voxel computational phantoms that have been developed at Helmholtz Zentrum München, Germany. Random and Latin hypercube sampling techniques were applied to sample parameters of biokinetic models and S values. The uncertainty factors, expressed as the square root of the 97.5th and 2.5th percentile ratios, for organ equivalent dose coefficients of 141Ce were found to be in the range of 1.2-5.1 and for 144Ce in the range of 1.2-7.4. The uncertainty factor of the detriment-weighted dose coefficient for 141Ce is 2.5 and for 144Ce 3.9. It is concluded that a general statistical method for calculating the uncertainty of dose coefficients was developed and applied to the lanthanide cerium. The dose uncertainties obtained provide improved dose coefficients for radiation risk analysis of humans. Furthermore, these uncertainties can be used to identify those parameters most important in internal dose calculations by applying sensitivity analyses.

Feasibility of reducing differences in estimated doses in nuclear medicine between a patient-specific and a reference phantom.

The feasibility of reducing the differences between patient-specific internal doses and doses estimated using reference phantoms was evaluated. Relatively simple adjustments to a polygon-surface ICRP adult male reference phantom were applied to fit selected individual dimensions using the software Rhinoceros®4.0. We tested this approach on two patient-specific phantoms: the biggest and the smallest phantoms from the Helmholtz Zentrum München library. These phantoms have unrelated anatomy and large differences in body-mass-index. Three models approximating each patient's anatomy were considered: the voxel and the polygon-surface ICRP adult male reference phantoms and the adjusted polygon-surface reference phantom. The Specific Absorbed Fractions (SAFs) for internal photon and electron sources were calculated with the Monte Carlo code EGSnrc. Employing the time-integrated activity coefficients of a radiopharmaceutical (S)-4-(3-18F-fluoropropyl)-l-glutamic acid and the calculated SAFs, organ absorbed-dose coefficients were computed following the formalism promulgated by the Committee on Medical Internal Radiation Dose. We compared the absorbed-dose coefficients between each patient-specific phantom and other models considered with emphasis on the cross-fire component. The corresponding differences for most organs were notably lower for the adjusted reference models compared to the case when reference models were employed. Overall, the proposed approach provided reliable dose estimates for both tested patient-specific models despite the pronounced differences in their anatomy. To capture the full range of inter-individual anatomic variability more patient-specific phantoms are required. The results of this test study suggest a feasibility of estimating patient-specific doses within a relative uncertainty of 25% or less using adjusted reference models, when only simple phantom scaling is applied.

Anthropomorphic dual-lattice voxel models for optimizing image quality and dose.

Using numerical simulations, the influence of various imaging parameters on the resulting image can be determined for various imaging technologies. To achieve this, visualization of fine tissue structures needed to evaluate the image quality with different radiation quality and dose is essential. The present work examines a method that employs simulations of the imaging process using Monte Carlo methods and a combination of a standard and higher resolution voxel models. A hybrid model, based on nonlinear uniform rational B-spline and polygon mesh surfaces, was constructed from an existing voxel model of a female patient of a resolution in the range of millimeters. The resolution of the hybrid model was [Formula: see text], i.e., substantially finer than that of the original model. Furthermore, a high resolution lung voxel model [[Formula: see text] voxel volume, slice thickness: [Formula: see text]] was developed from the specimen of a left lung lobe. This has been inserted into the hybrid model, substituting its left lung lobe and resulting in a dual-lattice geometry model. "Dual lattice" means, in this context, the combination of voxel models with different resolutions. Monte Carlo simulations of radiographic imaging were performed and the fine structure of the lung was easily recognizable.

Inclusion of thin target and source regions in alimentary and respiratory tract systems of mesh-type ICRP adult reference phantoms.

It is not feasible to define very small or complex organs and tissues in the current voxel-type adult reference computational phantoms of the International Commission on Radiological Protection (ICRP), which limit dose coefficients for weakly penetrating radiations. To address the problem, the ICRP is converting the voxel-type reference phantoms into mesh-type phantoms. In the present study, as a part of the conversion project, the micrometer-thick target and source regions in the alimentary and respiratory tract systems as described in ICRP Publications 100 and 66 were included in the mesh-type ICRP reference adult male and female phantoms. In addition, realistic lung airway models were simulated to represent the bronchial (BB) and bronchiolar (bb) regions. The electron specific absorbed fraction (SAF) values for the alimentary and respiratory tract systems were then calculated and compared with the values calculated with the stylized models of ICRP Publications 100 and 66. The comparisons show generally good agreement for the oral cavity, oesophagus, and BB, whereas for the stomach, small intestine, large intestine, extrathoracic region, and bb, there are some differences (e.g. up to ~9 times in the large intestine). The difference is mainly due to anatomical difference in these organs between the realistic mesh-type phantoms and the simplified stylized models. The new alimentary and respiratory tract models in the mesh-type ICRP reference phantoms preserve the topology and dimensions of the voxel-type ICRP phantoms and provide more reliable SAF values than the simplified models adopted in previous ICRP Publications.

Effect of blood activity on dosimetric calculations for radiopharmaceuticals.

The objective of this work was to investigate the influence of the definition of blood as a distinct source on organ doses, associated with the administration of a novel radiopharmaceutical for positron emission tomography-computed tomography (PET/CT) imaging-(S)-4-(3-18F-fluoropropyl)-L-glutamic acid (18F-FSPG). Personalised pharmacokinetic models were constructed based on clinical PET/CT images from five healthy volunteers and blood samples from four of them. Following an identifiability analysis of the developed compartmental models, person-specific model parameters were estimated using the commercial program SAAM II. Organ doses were calculated in accordance to the formalism promulgated by the Committee on Medical Internal Radiation Dose (MIRD) and the International Commission on Radiological Protection (ICRP) using specific absorbed fractions for photons and electrons previously derived for the ICRP reference adult computational voxel phantoms. Organ doses for two concepts were compared: source organ activities in organs parenchyma with blood as a separate source (concept-1); aggregate activities in perfused source organs without blood as a distinct source (concept-2). Aggregate activities comprise the activities of organs parenchyma and the activity in the regional blood volumes (RBV). Concept-1 resulted in notably higher absorbed doses for most organs, especially non-source organs with substantial blood contents, e.g. lungs (92% maximum difference). Consequently, effective doses increased in concept-1 compared to concept-2 by 3-10%. Not considering the blood as a distinct source region leads to an underestimation of the organ absorbed doses and effective doses. The pronounced influence of the blood even for a radiopharmaceutical with a rapid clearance from the blood, such as 18F-FSPG, suggests that blood should be introduced as a separate compartment in most compartmental pharmacokinetic models and blood should be considered as a distinct source in dosimetric calculations. Hence, blood samples should be included in all pharmacokinetic and dosimetric studies for new tracers if possible.

Development of skeletal system for mesh-type ICRP reference adult phantoms.

The reference adult computational phantoms of the international commission on radiological protection (ICRP) described in Publication 110 are voxel-type computational phantoms based on whole-body computed tomography (CT) images of adult male and female patients. The voxel resolutions of these phantoms are in the order of a few millimeters and smaller tissues such as the eye lens, the skin, and the walls of some organs cannot be properly defined in the phantoms, resulting in limitations in dose coefficient calculations for weakly penetrating radiations. In order to address the limitations of the ICRP-110 phantoms, an ICRP Task Group has been recently formulated and the voxel phantoms are now being converted to a high-quality mesh format. As a part of the conversion project, in the present study, the skeleton models, one of the most important and complex organs of the body, were constructed. The constructed skeleton models were then tested by calculating red bone marrow (RBM) and endosteum dose coefficients (DCs) for broad parallel beams of photons and electrons and comparing the calculated values with those of the original ICRP-110 phantoms. The results show that for the photon exposures, there is a generally good agreement in the DCs between the mesh-type phantoms and the original voxel-type ICRP-110 phantoms; that is, the dose discrepancies were less than 7% in all cases except for the 0.03 MeV cases, for which the maximum difference was 14%. On the other hand, for the electron exposures (⩽4 MeV), the DCs of the mesh-type phantoms deviate from those of the ICRP-110 phantoms by up to ~1600 times at 0.03 MeV, which is indeed due to the improvement of the skeletal anatomy of the developed skeleton mesh models.

New small-intestine modeling method for surface-based computational human phantoms.

When converting voxel phantoms to a surface format, the small intestine (SI), which is usually not accurately represented in a voxel phantom due to its complex and irregular shape on one hand and the limited voxel resolutions on the other, cannot be directly converted to a high-quality surface model. Currently, stylized pipe models are used instead, but they are strongly influenced by developer's subjectivity, resulting in unacceptable geometric and dosimetric inconsistencies. In this paper, we propose a new method for the construction of SI models based on the Monte Carlo approach. In the present study, the proposed method was tested by constructing the SI model for the polygon-mesh version of the ICRP reference male phantom currently under development. We believe that the new SI model is anatomically more realistic than the stylized SI models. Furthermore, our simulation results show that the new SI model, for both external and internal photon exposures, leads to dose values that are more similar to those of the original ICRP male voxel phantom than does the previously constructed stylized SI model.

Incorporation of detailed eye model into polygon-mesh versions of ICRP-110 reference phantoms.

The dose coefficients for the eye lens reported in ICRP 2010 Publication 116 were calculated using both a stylized model and the ICRP-110 reference phantoms, according to the type of radiation, energy, and irradiation geometry. To maintain consistency of lens dose assessment, in the present study we incorporated the ICRP-116 detailed eye model into the converted polygon-mesh (PM) version of the ICRP-110 reference phantoms. After the incorporation, the dose coefficients for the eye lens were calculated and compared with those of the ICRP-116 data. The results showed generally a good agreement between the newly calculated lens dose coefficients and the values of ICRP 2010 Publication 116. Significant differences were found for some irradiation cases due mainly to the use of different types of phantoms. Considering that the PM version of the ICRP-110 reference phantoms preserve the original topology of the ICRP-110 reference phantoms, it is believed that the PM version phantoms, along with the detailed eye model, provide more reliable and consistent dose coefficients for the eye lens.

ICRP Publication 116--the first ICRP/ICRU application of the male and female adult reference computational phantoms.

ICRP Publication 116 on 'Conversion coefficients for radiological protection quantities for external radiation exposures', provides fluence-to-dose conversion coefficients for organ-absorbed doses and effective dose for various types of external exposures (ICRP 2010 ICRP Publication 116). The publication supersedes the ICRP Publication 74 (ICRP 1996 ICRP Publication 74, ICRU 1998 ICRU Report 57), including new particle types and expanding the energy ranges considered. The coefficients were calculated using the ICRP/ICRU computational phantoms (ICRP 2009 ICRP Publication 110) representing the reference adult male and reference adult female (ICRP 2002 ICRP Publication 89), together with a variety of Monte Carlo codes simulating the radiation transport in the body. Idealized whole-body irradiation from unidirectional and rotational parallel beams as well as isotropic irradiation was considered for a large variety of incident radiations and energy ranges. Comparison of the effective doses with operational quantities revealed that the latter quantities continue to provide a good approximation of effective dose for photons, neutrons and electrons for the 'conventional' energy ranges considered previously (ICRP 1996, ICRU 1998), but not at the higher energies of ICRP Publication 116.

Overview of the ICRP/ICRU adult reference computational phantoms and dose conversion coefficients for external idealised exposures.

This paper reviews the ICRP Publications 110 and 116 describing the reference computational phantoms and dose conversion coefficients for external exposures. The International Commission on Radiological Protection (ICRP) in its 2007 Recommendations made several revisions to the methods of calculation of the protection quantities. In order to implement these recommendations, the DOCAL task group of the ICRP developed computational phantoms representing the reference adult male and female and then calculated a set of dose conversion coefficients for various types of idealised external exposures. This paper focuses on the dose conversion coefficients for neutrons and investigates their relationship with the conversion coefficients of the protection and operational quantities of ICRP Publication 74. Contributing factors to the differences between these sets of conversion coefficients are discussed in terms of the changes in phantoms employed and the radiation and tissue weighting factors.

Organ doses from environmental exposures calculated using voxel phantoms of adults and children.

This paper presents effective and organ dose conversion coefficients for members of the public due to environmental external exposures, calculated using the ICRP adult male and female reference computational phantoms as well as voxel phantoms of a baby, two children and four adult individual phantoms--one male and three female, one of them pregnant. Dose conversion coefficients are given for source geometries representing environmental radiation exposures, i.e. whole body irradiations from a volume source in air, representing a radioactive cloud, a plane source in the ground at a depth of 0.5 g cm⁻², representing ground contamination by radioactive fall-out, and uniformly distributed natural sources in the ground. The organ dose conversion coefficients were calculated employing the Monte Carlo code EGSnrc simulating the photon transport in the voxel phantoms, and are given as effective and equivalent doses normalized to air kerma free-in-air at height 1 m above the ground in Sv Gy(-1). The findings showed that, in general, the smaller the body mass of the phantom, the higher the dose. The difference in effective dose between an adult and an infant is 80-90% at 50 keV and less than 40% above 100 keV. Furthermore, dose equivalent rates for photon exposures of several radionuclides for the above environmental exposures were calculated with the most recent nuclear decay data. Data are shown for effective dose, thyroid, colon and red bone marrow. The results are expected to facilitate regulation of exposure to radiation, relating activities of radionuclides distributed in air and ground to dose of the public due to external radiation as well as the investigation of the radiological effects of major radiation accidents such as the recent one in Fukushima and the decision making of several committees.

Effective dose conversion coefficients for radionuclides exponentially distributed in the ground.

In order to provide fundamental data required for dose evaluation due to environmental exposures, effective dose conversion coefficients, that is, the effective dose rate per unit activity per unit area, were calculated for a number of potentially important radionuclides, assuming an exponential distribution in ground, over a wide range of relaxation depths. The conversion coefficients were calculated for adults and a new-born baby on the basis of dosimetric methods that the authors and related researchers have previously developed, using Monte Carlo simulations and anthropomorphic computational phantoms. The differences in effective dose conversion coefficients due to body size between the adult and baby phantoms were found to lie within 50 %, for most cases; however, for some low energies, differences could amount to a factor of 3. The effective dose per unit source intensity per area was found to decrease by a factor of 2-5, for increasing relaxation depths from 0 to 5 g/cm(2), above a source energy of 50 keV. It is also shown that implementation of the calculated coefficients into the computation of the tissue weighting factors and the adult reference computational phantoms of ICRP Publication 103 does not significantly influence the effective dose conversion coefficients of the environment. Consequently, the coefficients shown in this paper could be applied for the evaluation of effective doses, as defined according to both recommendations of ICRP Publications 103 and 60.

Electron specific absorbed fractions for the adult male and female ICRP/ICRU reference computational phantoms.

The calculation of radiation dose from internally incorporated radionuclides is based on so-called absorbed fractions (AFs) and specific absorbed fractions (SAFs). SAFs for monoenergetic electrons were calculated for 63 source regions and 67 target regions using the new male and female adult reference computational phantoms adopted by the ICRP and ICRU and the Monte Carlo radiation transport programme package EGSnrc. The SAF values for electrons are opposed to the simplifying assumptions of ICRP Publication 30. The previously applied assumption of electrons being fully absorbed in the source organ itself is not always true at electron energies above approximately 300-500 keV. High-energy electrons have the ability to leave the source organ and, consequently, the electron SAFs for neighbouring organs can reach the same magnitude as those for photons for electron energies above 1 MeV. The reciprocity principle known for photons can be extended to electron SAFs as well, thus making cross-fire electron SAFs mass-independent. To quantify the impact of the improved electron dosimetry in comparison to the dosimetry using the simple assumptions of ICRP Publication 30, absorbed doses per administered activity of three radiopharmaceuticals were evaluated with and without explicit electron transport. The organ absorbed doses per administered activity for the two evaluation methods agree within 2%-3% for most organs for radionuclides with decay spectra having electron energies below a few hundred keV and within approximately 20% if higher electron energies are involved. An important exception is the urinary bladder wall, where the dose is overestimated by 60-150% using the simplified ICRP 30 approach for the radiopharmaceuticals of this study.

Fluence-to-dose conversion coefficients for neutrons and protons calculated using the PHITS code and ICRP/ICRU adult reference computational phantoms.

The fluence to organ-dose and effective-dose conversion coefficients for neutrons and protons with energies up to 100 GeV was calculated using the PHITS code coupled to male and female adult reference computational phantoms, which are to be released as a common ICRP/ICRU publication. For the calculation, the radiation and tissue weighting factors, w(R) and w(T), respectively, as revised in ICRP Publication 103 were employed. The conversion coefficients for effective dose equivalents derived using the radiation quality factors of both Q(L) and Q(y) relationships were also estimated, utilizing the functions for calculating the probability densities of the absorbed dose in terms of LET (L) and lineal energy (y), respectively, implemented in PHITS. By comparing these data with the corresponding data for the effective dose, we found that the numerical compatibilities of the revised w(R) with the Q(L) and Q(y) relationships are fairly established. The calculated data of these dose conversion coefficients are indispensable for constructing the radiation protection systems based on the new recommendations given in ICRP103 for aircrews and astronauts, as well as for workers in accelerators and nuclear facilities.

Patient-specific scaling of reference S-values for cross-organ radionuclide S-values: what is appropriate?

The Medical Internal Radiation Dose Committee (MIRD) formalism assumes reference mass values for the organs (source and target) and the total body. MIRD publication 11 provides guidance on how patient-specific scaling of reference radionuclide S-values are to be performed for the electron component of the emission spectrum. However, guidance on patient-specific scaling of the photon contributions to the S-value is given only for those cases where the source and target organs are either far apart or are the same. The photon component of the S-value is derived from photon-Specific Absorbed Fractions (SAFs). These are obtained by Monte Carlo calculation of photon transport. The objective of this work is to verify the MIRD 11 guidance and to examine the relationship between photon SAFs and source/target organ mass when the conditions listed above do not apply. Furthermore, the scaling for photon cross-dose to distributed organs is at present not defined due to lack of data for models other than the reference model. The validity of mass scaling for cross irradiation from near and distant photons sources, especially for Red Bone Marrow (RBM) as a target tissue is also investigated. This is achieved by comparing Monte Carlo-derived SAFs for different source organs to RBM across the GSF voxel phantom series. The results show that, for photon energies greater than 100 keV, the SAF of most source organs to RBM need not be corrected for target mass (error < 5%). In contrast to the results obtained for well-defined source organs, the SAF for RBM irradiating RBM gives a deviation of up to 16% across the different GSF voxel phantoms.

A software tool for modification of human voxel models used for application in radiation protection.

This note describes a new software tool called 'VolumeChange' that was developed to modify the masses and location of organs of virtual human voxel models. A voxel model is a three-dimensional representation of the human body in the form of an array of identification numbers that are arranged in slices, rows and columns. Each entry in this array represents a voxel; organs are represented by those voxels having the same identification number. With this tool, two human voxel models were adjusted to fit the reference organ masses of a male and a female adult, as defined by the International Commission on Radiological Protection (ICRP). The alteration of an already existing voxel model is a complicated process, leading to many problems that have to be solved. To solve those intricacies in an easy way, a new software tool was developed and is presented here. If the organs are modified, no bit of tissue, i.e. voxel, may vanish nor should an extra one appear. That means that organs cannot be modified without considering the neighbouring tissue. Thus, the principle of organ modification is based on the reassignment of voxels from one organ/tissue to another; actually deleting and adding voxels is only possible at the external surface, i.e. skin. In the software tool described here, the modifications are done by semi-automatic routines but including human control. Because of the complexity of the matter, a skilled person has to validate that the applied changes to organs are anatomically reasonable. A graphical user interface was designed to fulfil the purpose of a comfortable working process, and an adequate graphical display of the modified voxel model was developed. Single organs, organ complexes and even whole limbs can be edited with respect to volume, shape and location.

Estimation of patient dose from radiopharmaceuticals using voxel models.

The aim of this study was to demonstrate the advantages of patient dosimetry using voxel models and to present sets of dose estimates for patients of different gender and size. These models offer greater realism with respect to organ shape and topology than the well-established Medical Internal Radiation Dose (MIRD)-type mathematical models. At the National Research Centre for Environment and Health (GSF), specific absorbed fractions have been previously calculated for 4 male and 3 female voxel models, representing different age and stature, for a wide range of source organs. For this study, estimates both for established and new radiopharmaceuticals were performed using biokinetic data from International Commission on Radiological Protection (ICRP). The above calculations allowed for comparison to the MIRD technique in relation to the resulting absorbed organ and effective doses. Furthermore, data sets representing a range of voxel phantoms were investigated. It was found that dose differences among the voxel models can amount up to a factor of 3.