Proof-of-concept of DosiTest: A virtual multicentric clinical trial for assessing uncertainties in molecular radiotherapy dosimetry.

Clinical dosimetry in molecular radiotherapy (MRT) is a multi-step procedure, prone to uncertainties at every stage of the dosimetric workflow. These are difficult to assess, especially as some are complex or even impossible to measure experimentally. The DosiTest project was initiated to assess the variability associated with clinical dosimetry, by setting up a 'virtual' multicentric clinical dosimetry trial based on Monte Carlo (MC) modelling. A reference patient model with a realistic geometry and activity input for a specific tracer is considered. Reference absorbed dose rate distribution maps are generated at various time-points from MC modelling, combining precise information on density and activity distributions (voxel wise). Then, centre-specific calibration and patient SPECT/CT datasets are modelled, on which the clinical centres can perform clinical (i.e. image-based) dosimetry. The results of this dosimetric analysis can be benchmarked against the reference dosimetry to assess the variability induced by implementing different clinical dosimetry approaches. The feasibility of DosiTest is presented here for a clinical situation of therapeutic administration of 177Lu-DOTATATE (Lutathera®) peptide receptor radionuclide therapy (PRRT). From a real patient dataset composed of 5 SPECT/CT images and associated calibrations, we generated the reference absorbed dose rate images with GATE. Then, simulated SPECT/CT image generation based on GATE was performed, both for a calibration phantom and virtual patient images. Based on this simulated dataset, image-based dosimetry could be performed, and compared with reference dosimetry. The good agreement, between real and simulated images, and between reference and image-based dosimetry established the proof of concept of DosiTest.

Clinical implementation of PLANET® Dose for dosimetric assessment after [177Lu]Lu-DOTA-TATE: comparison with Dosimetry Toolkit® and OLINDA/EXM® V1.0.

BACKGROUND: The aim of this study was to compare a commercial dosimetry workstation (PLANET® Dose) and the dosimetry approach (GE Dosimetry Toolkit® and OLINDA/EXM® V1.0) currently used in our department for quantification of the absorbed dose (AD) to organs at risk after peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE. METHODS: An evaluation on phantom was performed to determine the SPECT calibration factor variations over time and to compare the Time Integrated Activity Coefficients (TIACs) obtained with the two approaches. Then, dosimetry was carried out with the two tools in 21 patients with neuroendocrine tumours after the first and second injection of 7.2 ± 0.2 GBq of [177Lu]Lu-DOTA-TATE (40 dosimetry analyses with each software). SPECT/CT images were acquired at 4 h, 24 h, 72 h and 192 h post-injection and were reconstructed using the Xeleris software (General Electric). The liver, spleen and kidneys masses and TIACs were determined using Dosimetry Toolkit® (DTK) and PLANET® Dose. The ADs were calculated using OLINDA/EXM® V1.0 and the Local Deposition Method (LDM) or Dose voxel-Kernel convolution (DK) on PLANET® Dose. RESULTS: With the phantom, the 3D calibration factors showed a slight variation (0.8% and 3.3%) over time, and TIACs of 225.19 h and 217.52 h were obtained with DTK and PLANET® Dose, respectively. In patients, the root mean square deviation value was 8.9% for the organ masses, 8.1% for the TIACs, and 9.1% and 7.8% for the ADs calculated with LDM and DK, respectively. The Lin's concordance correlation coefficient was 0.99 and the Bland-Altman plot analysis estimated that the AD value difference between methods ranged from - 0.75 to 0.49 Gy, from - 0.20 to 0.64 Gy, and from - 0.43 to 1.03 Gy for 95% of the 40 liver, kidneys and spleen dosimetry analyses. The dosimetry method had a minor influence on AD differences compared with the image registration and organ segmentation steps. CONCLUSIONS: The ADs to organs at risk obtained with the new workstation PLANET® Dose are concordant with those calculated with the currently used software and in agreement with the literature. These results validate the use of PLANET® Dose in clinical routine for patient dosimetry after targeted radiotherapy with [177Lu]Lu-DOTA-TATE.

Scientific Developments in Imaging and Dosimetry for Molecular Radiotherapy.

Molecular radiotherapy is a rapidly developing field with new vector and isotope combinations continually added to market. As with any radiotherapy treatment, it is vital that the absorbed dose and toxicity profile are adequately characterised. Methodologies for absorbed dose calculations for radiopharmaceuticals were generally developed to characterise stochastic effects and not suited to calculations on a patient-specific basis. There has been substantial scientific and technological development within the field of molecular radiotherapy dosimetry to answer this challenge. The development of imaging systems and advanced processing techniques enable the acquisition of accurate measurements of radioactivity within the body. Activity assessment combined with dosimetric models and radiation transport algorithms make individualised absorbed dose calculations not only feasible, but commonplace in a variety of commercially available software packages. The development of dosimetric parameters beyond the absorbed dose has also allowed the possibility to characterise the effect of irradiation by including biological parameters that account for radiation absorbed dose rates, gradients and spatial and temporal energy distribution heterogeneities. Molecular radiotherapy is in an exciting time of its development and the application of dosimetry in this field can only have a positive influence on its continued progression.

Monte Carlo dose calculation in presence of low-density media: Application to lung SBRT treated during DIBH.

PURPOSE: Commercial algorithms used in Radiotherapy include approximations that are generally acceptable. However their limits can be seen when confronted with small fields and low-density media. These conditions exist during the treatment of lung cancers with Stereotactic Body Radiation Therapy (SBRT) achieved with the "Deep Inspiration Breath Hold" (DIBH) technique. A Monte Carlo (MC) model of a linear accelerator was used to assess the performance of two algorithms (Varian Acuros and AAA) in these conditions. This model is validated using phantoms with different densities. Lastly, results for SBRT cases are compared to both Acuros and AAA. METHODS: A Varian TrueBeam linac was modeled using GATE/Geant4 and validated by comparing dose distributions for simple fields to measurements in water and in heterogeneous phantoms composed of PMMA and two types of cork (corresponding to lung densities during free-breathing and DIBH). Experimental measurements are also compared to AAA and Acuros. Finally, results of Acuros/AAA are compared to MC for a clinical case (SBRT during DIBH). RESULTS: Based on 1D gamma index comparisons with measurements in water, the TrueBeam model was validated (>97% of points passed this test). In heterogeneous phantoms, and in particular for small field sizes, very low density (0.12g.cm-3) and at the edge of the field, MC model was still in good agreement with measurements whilst AAA and Acuros showed discrepancies. With the patient CT, similar differences between MC and AAA/Acuros were observed for static fields but disappeared using an SBRT arc field. CONCLUSIONS: Our MC model is validated and limits of commercial algorithms are shown in very low densities.

Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application.

Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

Multi-scale hybrid models for radiopharmaceutical dosimetry with Geant4.

The accuracy of radiopharmaceutical absorbed dose distributions computed through Monte Carlo (MC) simulations is mostly limited by the low spatial resolution of 3D imaging techniques used to define the simulation geometry. This issue also persists with the implementation of realistic hybrid models built using polygonal mesh and/or NURBS as they require to be simulated in their voxel form in order to reduce computation times. The existing trade-off between voxel size and simulation speed leads on one side, in an overestimation of the size of small radiosensitive structures such as the skin or hollow organs walls and, on the other, to unnecessarily detailed voxelization of large, homogeneous structures.We developed a set of computational tools based on VTK and Geant4 in order to build multi-resolution organ models. Our aim is to use different voxel sizes to represent anatomical regions of different clinical relevance: the MC implementation of these models is expected to improve spatial resolution in specific anatomical structures without significantly affecting simulation speed. Here we present the tools developed through a proof of principle example. Our approach is validated against the standard Geant4 technique for the simulation of voxel geometries.

The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research.

The assessment and management of risks associated with exposures to ionising radiation are defined by the general radiological protection system, proposed by the International Commission on Radiological Protection (ICRP). This system is regarded by a large majority of users as a robust system although there are a number of dissenting voices, claiming that it is not suitable for estimating the risks resulting from internal exposures. One of the specific issues of internal exposure involves short-range radiations such as Auger and beta particles. Auger- and beta-emitting radionuclides can be distributed preferentially in certain tissue structures and even in certain cellular organelles, according to their chemical nature and the vector with which they are associated. Given the limited range of the low-energy electrons in biological matter, this heterogeneous distribution can generate highly localised energy depositions and exacerbate radiotoxic responses at cellular level. These particularities in energy distribution and cellular responses are not taken into account by the conventional methods for the assessment of risk.Alternative systems have been proposed, based on dosimetry conducted at the cellular or even molecular level, whose purpose is to determine the energy deposition occurring within the DNA molecule. However, calculation of absorbed doses at the molecular level is not sufficient to ensure a better assessment of the risks incurred. Favouring such a microdosimetric approach for the risk assessments would require a comprehensive knowledge of the biological targets of radiation, the dose-response relationships at the various levels of organisation, and the mechanisms leading from cellular energy deposition to the appearance of a health detriment. The required knowledge is not fully available today and it is not yet possible to link an intracellular energy deposition to a probability of occurrence of health effects or to use methods based on cellular dosimetry directly.The imperfections of the alternative approaches proposed so far should not discourage efforts. Protection against exposure to Auger and low-energy beta emitters would benefit from mechanistic studies, dedicated to the study of energy depositions of the radionuclides in various cellular structures, but also from radiotoxicological studies to define the relative biological effectiveness of the various Auger emitters used in medicine and of certain low-energy beta emitters, whose behaviour may depend greatly on their chemical form during intake. The scientific expertise, as well as the human and physical resources needed to conduct these studies, is available. They could be now mobilised into international low-dose research programmes, in order to ultimately improve the protection of people exposed to these specific radionuclides.

Comparisons of dosimetric approaches for fractionated radioimmunotherapy of non-Hodgkin lymphoma.

AIM: The aim of this study was to compare different dosimetric approaches on therapy naïve patients enrolled in a multicentre fractionated radioimmunotherapy trial, to determine which methodological approach correlates with bone marrow toxicity. METHODS: Twenty-height non-Hodgkin lymphoma patients were treated with one or two fractions of 90Y-Ibritumomab-Tiuxetan (11.1 MBq/kg) 8 to 12 weeks apart in four different institutions. Quantitative imaging with 111In-Ibritumomab-Tiuxetan (185 MBq) was performed at 0, 1, 4 and 7 days after infusion, starting two weeks before the therapeutic administration. A whole-body (WB) CT scan was also acquired prior to the 111In-Ibritumomab injection, for attenuation correction purposes and was segmented to derive patient-specific organ masses. All dosimetry processing was centralized in a single institution. The first method (M_2D) was based on geometric mean WB scans, corrected for attenuation, scatter and organs superposition. The second method (M_2.5D) was based on the computed assisted matrix inversion approach and used segmented CT scans. The third method (M_3D) used iterative reconstruction of tomographic scans, corrected for attenuation, scatter and collimator response. Absorbed doses were estimated for lungs, liver, kidneys and spleen using MIRD S values adjusted for organ masses. Bone marrow (BM) absorbed doses were evaluated according to imaging methods (3) and compared to blood-based approaches. RESULTS: For some patients, organ masses such as liver or spleen significantly differed from male/female reference masses, whereas lungs and kidneys masses were relatively constant. Except for lungs, absorbed doses estimated by M_2D were higher than those from M_2.5D and these, in turn, were higher that those calculated from M_3D (Wilcoxon P<8.6e-4). Median organ absorbed dose estimates were equivalent for both fractions except for the spleen. In fact, spleen absorbed doses for the second fraction were lower than those for the first fraction, regardless of the approach. Possible explanations are that patient spleen masses were kept constant for analysis of both fractions and/or that spleen uptake was lowered after the first fraction. Estimation of BM absorbed doses from blood sampling was unable to predict platelet toxicity, but image-based methods performed better. Additionally, for most organs, the absorbed dose delivered by the first fraction could predict that delivered by the second fraction. CONCLUSION: These results confirm that different acquisition/processing protocols will lead to statistically different absorbed doses. Additionally, image-based dosimetric approaches are needed in order to correlate absorbed dose to bone marrow toxicity.

EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting.

Many recent publications in nuclear medicine contain data on dosimetric findings for existing and new diagnostic and therapeutic agents. In many of these articles, however, a description of the methodology applied for dosimetry is lacking or important details are omitted. The intention of the EANM Dosimetry Committee is to guide the reader through a series of suggestions for reporting dosimetric approaches. The authors are aware of the large amount of data required to report the way a given clinical dosimetry procedure was implemented. Another aim of this guidance document is to provide comprehensive information for preparing and submitting publications and reports containing data on internal dosimetry. This guidance document also contains a checklist which could be useful for reviewers of manuscripts submitted to scientific journals or for grant applications. In addition, this document could be used to decide which data are useful for a documentation of dosimetry results in individual patient records. This may be of importance when the approval of a new radiopharmaceutical by official bodies such as EMA or FDA is envisaged.

Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. I. Presentation and validation of a microdosimetric model.

A microdosimetric model that makes it possible to consider the numerous biological and physical parameters of cellular alpha-particle irradiation by radiolabeled mAbs was developed. It allows for the calculation of single-hit and multi-hit distributions of specific energy within a cell nucleus or a whole cell in any irradiation configuration. Cells are considered either to be isolated or to be packed in a monolayer or a spheroid. The method of calculating energy deposits is analytical and is based on the continuous-slowing-down approximation. A model of cell survival, calculated from the microdosimetric spectra and the microdosimetric radiosensitivity, z(0), was also developed. The algorithm of calculations was validated by comparison with two general Monte Carlo codes: MCNPX and Geant4. Microdosimetric spectra determined by these three codes showed good agreement for numerous geometrical configurations. The analytical method was far more efficient in terms of calculation time: A gain of more than 1000 was observed when using our model compared with Monte Carlo calculations. Good agreements were also observed with previously published results.

Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. II. Application of the microdosimetric model to experimental results.

A microdosimetric model was used to analyze the results of experimental studies on cells of two lymphoid cell lines (T2 and Ada) irradiated with (213)Bi-radiolabeled antibodies. These antibodies targeted MHC/peptide complexes. The density of target antigen could be modulated by varying the concentration of the peptide loaded onto the cells. This offered the possibility of changing the ratio of specific (from cell-bound antibody) to non-specific (from antibody present in the supernatant) irradiation. For both cell lines, survival plotted as a function of the mean absorbed dose was a decreasing exponential. For the T2 cells, the microdosimetric sensitivity calculated for the whole cell was equal whether the irradiation was non-specific (z(0) = 0.12 +/- 0.02 Gy) or specific (z(0) = 0.12 +/- 0.09 Gy). Similar results were obtained for Ada cells. These results constitute a biological validation of the microdosimetric model. For both cells, the measured cell mortality was greater than the percentage of hit cells calculated with the model at low mean absorbed doses. This observation thus suggests bystander effects. It poses the question of the relevance of the mean absorbed dose to the cell nuclei. A new concept in cellular dosimetry taking into account cytoplasm or membrane irradiation and bystander modeling appears to be needed.

S-factor calculations for mouse models using Monte-Carlo simulations.

AIM: Targeted radionuclide therapy applications require the use of small animals for preclinical experiments. Accurate dose estimation is needed in such animals to explore and analyze the toxicity of injected radiopharmaceuticals. We developed two numerical models to allow for a more accurate mouse dosimetry. METHODS: A frozen nude mouse (30 g) was sliced and digital photographs were taken during the operation. More than 30 organs and tissues were identified and manually segmented. A digital (voxel-based) and a mathematical model were constructed from the segmented images. Important organs were simulated as radiation sources using the Monte-Carlo code MCNP4C. Mono-energetic photons from 0.005 to 2 MeV, and monoenergetic electrons from 0.1 to 2.5 MeV were simulated. Activity was supposed to be uniform in all source organs. RESULTS: Results from monoenergetic emissions were integrated over emission spectra. Radionuclide S-factors (Gy/Bq.s) were calculated by taking into account both electron and photon contributions. A comparison of the results obtained with either a voxel-based or mathematical model was carried out. The voxel-based model was then used to revise dosimetric results, obtained previously under the assumption that all emitted energy was absorbed locally. For (188)Re, the self-absorbed doses in xenografted tumors were 39-69% lower than that obtained by assuming local energy deposition. CONCLUSION: The voxel-based models represent more realistic anatomic approach. The rapid advancement of computer science and new features added to Monte-Carlo codes permit considerable reduction of computational run time. Cross-doses should not be neglected when medium to high energy beta emitters are being used for preclinical experiments on mice.

A voxel-based mouse for internal dose calculations using Monte Carlo simulations (MCNP).

Murine models are useful for targeted radiotherapy pre-clinical experiments. These models can help to assess the potential interest of new radiopharmaceuticals. In this study, we developed a voxel-based mouse for dosimetric estimates. A female nude mouse (30 g) was frozen and cut into slices. High-resolution digital photographs were taken directly on the frozen block after each section. Images were segmented manually. Monoenergetic photon or electron sources were simulated using the MCNP4c2 Monte Carlo code for each source organ, in order to give tables of S-factors (in Gy Bq-1 s-1) for all target organs. Results obtained from monoenergetic particles were then used to generate S-factors for several radionuclides of potential interest in targeted radiotherapy. Thirteen source and 25 target regions were considered in this study. For each source region, 16 photon and 16 electron energies were simulated. Absorbed fractions, specific absorbed fractions and S-factors were calculated for 16 radionuclides of interest for targeted radiotherapy. The results obtained generally agree well with data published previously. For electron energies ranging from 0.1 to 2.5 MeV, the self-absorbed fraction varies from 0.98 to 0.376 for the liver, and from 0.89 to 0.04 for the thyroid. Electrons cannot be considered as 'non-penetrating' radiation for energies above 0.5 MeV for mouse organs. This observation can be generalized to radionuclides: for example, the beta self-absorbed fraction for the thyroid was 0.616 for I-131; absorbed fractions for Y-90 for left kidney-to-left kidney and for left kidney-to-spleen were 0.486 and 0.058, respectively. Our voxel-based mouse allowed us to generate a dosimetric database for use in preclinical targeted radiotherapy experiments.

Validation of a personalized dosimetric evaluation tool (Oedipe) for targeted radiotherapy based on the Monte Carlo MCNPX code.

Dosimetric studies are necessary for all patients treated with targeted radiotherapy. In order to attain the precision required, we have developed Oedipe, a dosimetric tool based on the MCNPX Monte Carlo code. The anatomy of each patient is considered in the form of a voxel-based geometry created using computed tomography (CT) images or magnetic resonance imaging (MRI). Oedipe enables dosimetry studies to be carried out at the voxel scale. Validation of the results obtained by comparison with existing methods is complex because there are multiple sources of variation: calculation methods (different Monte Carlo codes, point kernel), patient representations (model or specific) and geometry definitions (mathematical or voxel-based). In this paper, we validate Oedipe by taking each of these parameters into account independently. Monte Carlo methodology requires long calculation times, particularly in the case of voxel-based geometries, and this is one of the limits of personalized dosimetric methods. However, our results show that the use of voxel-based geometry as opposed to a mathematically defined geometry decreases the calculation time two-fold, due to an optimization of the MCNPX2.5e code. It is therefore possible to envisage the use of Oedipe for personalized dosimetry in the clinical context of targeted radiotherapy.

Current developments at IRSN on computational tools dedicated to assessing doses for both internal and external exposure.

The paper presents the OEDIPE (French acronym that stands for tool for personalised internal dose assessment) and SESAME (for simulation of external source accident with medical images) computational tools, dedicated to internal and external dose assessment, respectively, and currently being developed at the Institute for Radiological Protection and Nuclear Safety. The originality of OEDIPE and SESAME, by using voxel phantoms in association with Monte Carlo codes, lies in their ability to construct personalised voxel phantoms from medical images and automatically generate the Monte Carlo input file and visualise the expected results. OEDIPE simulates in vivo measurements to improve their calibration, and calculates the dose distribution taking both internal contamination and internal radiotherapy cases into account. SESAME enables radiological overexposure doses to be reconstructed, as also victim, source and accident environment modelling. The paper presents the principles on which these tools function and an overview of specificities and results linked to their fields of application.

Dosimetric comparison of Monte Carlo codes (EGS4, MCNP, MCNPX) considering external and internal exposures of the Zubal phantom to electron and photon sources.

This paper aims at comparing dosimetric assessments performed with three Monte Carlo codes: EGS4, MCNP4c2 and MCNPX2.5e, using a realistic voxel phantom, namely the Zubal phantom, in two configurations of exposure. The first one deals with an external irradiation corresponding to the example of a radiological accident. The results are obtained using the EGS4 and the MCNP4c2 codes and expressed in terms of the mean absorbed dose (in Gy per source particle) for brain, lungs, liver and spleen. The second one deals with an internal exposure corresponding to the treatment of a medullary thyroid cancer by 131I-labelled radiopharmaceutical. The results are obtained by EGS4 and MCNPX2.5e and compared in terms of S-values (expressed in mGy per kBq and per hour) for liver, kidney, whole body and thyroid. The results of these two studies are presented and differences between the codes are analysed and discussed.

New thermoluminescent dosimeters (TLD): optimization and characterization of TLD threads sterilizable by autoclave.

To improve the performance of mono-extruded TLD threads as a dosimetric thermoluminescent tool (French Patent 9903729), a new process was developed by co-extrusion methodology leading to threads of 600 microm diameter with a 50 microm homogeneous polypropylene sheath. In this optimization work, study of parameters such as LiF:Mg,Cu,P powder granulometry, load rate and proportion of components led to an increased sensitivity of around 40%. Moreover, the co-extrusion technique allowed the threads to be sterilized by humid steam (134 degrees C/18 min) without significant variation of the linearity response between 0 and 30 Gy after gamma irradiation (60Co).