Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Symposium on molecular radiotherapy dosimetry: The first of a series?

The EFOMP Special Interest Group for Radionuclide Internal Dosimetry (SIG_FRID) organised its first scientific meeting, the Symposium on Molecular Radiotherapy Dosimetry, in Athens on November 9th-11th 2023. The Symposium was hosted by the Hellenic Association of Medical Physicists and the National and Kapodistrian University of Athens. This meeting gathered more than 180 scientists from 28 countries. Scientific, clinical and regulatory aspects were addressed by 8 invited experts. Two continuous professional development sessions were organised. A special round table gathering medical physics experts, physicians regulatory authority experts and patient representatives addressed the possibilities to increase clinical dosimetry dissemination. The event was supported by companies and a specific industry session allowed sponsors to present their products, innovations and future perspective in this field.

Technical note: Impact of dose voxel kernel (DVK) values on dosimetry estimates in 177 Lu and 90 Y radiopharmaceutical therapy (RPT) applications.

BACKGROUND: Radiopharmaceutical therapy (RPT) is an increasingly adopted modality for treating cancer. There is evidence that the optimization of the treatment based on dosimetry can improve outcomes. However, standardization of the clinical dosimetry workflow still represents a major effort. Among the many sources of variability, the impact of using different Dose Voxel Kernels (DVKs) to generate absorbed dose (AD) maps by convolution with the time-integrated activity (TIA) distribution has not been systematically investigated. PURPOSE: This study aims to compare DVKs and assess the differences in the ADs when convolving the same TIA map with different DVKs. METHODS: DVKs of 3 × 3 × 3 mm3 sampling-nine for 177 Lu, nine for 90 Y-were selected from those most used in commercial/free software or presented in prior publications. For each voxel within a 11 × 11 × 11 matrix, the coefficient of variation (CoV) and the percentage difference between maximum and minimum values (% maximum difference) were calculated. The total absorbed dose per decay (SUM), calculated as the sum of all the voxel values in each kernel, was also compared. Publicly available quantitative SPECT images for two patients treated with 177 Lu-DOTATATE and PET images for two patients treated with 90 Y-microspheres were used, including organs at risk (177 Lu: kidneys; 90 Y: liver and healthy liver) and tumors' segmentations. For each patient, the mean AD to the volumes of interest (VOIs) was calculated using the different DVKs, the same TIA map and the same software tool for dose convolution, thereby focusing on the DVK impact. For each VOI, the % maximum difference of the mean AD between maximum and minimum values was computed. RESULTS: The CoV (% maximum difference) in voxels of normalized coordinates [0,0,0], [0,1,0], and [0,1,1] were 5%(21%), 9%(35%), and 10%(46%) for the 177 Lu DVKs. For the case of 90 Y, these values were 2%(9%), 4%(14%), and 4%(16%). The CoV (% maximum difference) for SUM was 9%(33%) for 177 Lu, and 4%(15%) for 90 Y. The variability of the mean tumor and organ AD was up to 19% and 15% in 177 Lu-DOTATATE and 90 Y-microspheres patients, respectively. CONCLUSIONS: This study showed a considerable AD variability due exclusively to the use of different DVKs. A concerted effort by the scientific community would contribute to decrease these discrepancies, strengthening the consistency of AD calculation in RPT.

Quality Assurance Considerations in Radiopharmaceutical Therapy Dosimetry Using PLANETDose: An International Atomic Energy Agency Study.

Implementation of radiopharmaceutical therapy dosimetry varies depending on the clinical application, dosimetry protocol, software, and ultimately the operator. Assessing clinical dosimetry accuracy and precision is therefore a challenging task. This work emphasizes some pitfalls encountered during a structured analysis, performed on a single-patient dataset consisting of SPECT/CT images by various participants using a standard protocol and clinically approved commercial software. Methods: The clinical dataset consisted of the dosimetric study of a patient administered with [177Lu]Lu-DOTATATE at Tygerberg Hospital, South Africa, as a part of International Atomic Energy Agency-coordinated research project E23005. SPECT/CT images were acquired at 5 time points postinjection. Patient and calibration images were reconstructed on a workstation, and a calibration factor of 122.6 Bq/count was derived independently and provided to the participants. A standard dosimetric protocol was defined, and PLANETDose (version 3.1.1) software was installed at 9 centers to perform the dosimetry of 3 treatment cycles. The protocol included rigid image registration, segmentation (semimanual for organs, activity threshold for tumors), and dose voxel kernel convolution of activity followed by absorbed dose (AD) rate integration to obtain the ADs. Iterations of the protocol were performed by participants individually and within collective training, the results of which were analyzed for dosimetric variability, as well as for quality assurance and error analysis. Intermediary checkpoints were developed to understand possible sources of variation and to differentiate user error from legitimate user variability. Results: Initial dosimetric results for organs (liver and kidneys) and lesions showed considerable interoperator variability. Not only was the generation of intermediate checkpoints such as total counts, volumes, and activity required, but also activity-to-count ratio, activity concentration, and AD rate-to-activity concentration ratio to determine the source of variability. Conclusion: When the same patient dataset was analyzed using the same dosimetry procedure and software, significant disparities were observed in the results despite multiple sessions of training and feedback. Variations due to human error could be minimized or avoided by performing intensive training sessions, establishing intermediate checkpoints, conducting sanity checks, and cross-validating results across physicists or with standardized datasets. This finding promotes the development of quality assurance in clinical dosimetry.

Implementation of dosimetry for molecular radiotherapy; results from a European survey.

PURPOSE: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe. METHODS: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022. Questions addressed the application of 16 different MRTs, the availability and involvement of medical physicists, software used, quality assurance, as well as the target regions for dosimetry, whether treatment planning and/or verification were performed, and the dosimetric methods used. RESULTS: A total of 173 responses suitable for analysis was received from centres performing MRT, geographically distributed over 27 European countries. Of these, 146 centres (84 %) indicated to perform some form of dosimetry, and 97 % of these centres had a medical physicist available and almost always involved in dosimetry. The most common MRTs were 131I-based treatments for thyroid diseases and thyroid cancer, and [223Ra]RaCl2 for bone metastases. The implementation of dosimetry varied widely between therapies, from almost all centres performing dosimetry-based planning for microsphere treatments to none for some of the less common treatments (like 32P sodium-phosphate for myeloproliferative disease and [89Sr]SrCl2 for bone metastases). CONCLUSIONS: Over the last years, implementation of dosimetry, both for pre-therapeutic treatment planning and post-therapy absorbed dose verification, increased for several treatments, especially for microsphere treatments. For other treatments that have moved from research to clinical routine, the use of dosimetry decreased in recent years. However, there are still large differences both across and within countries.

EFOMP policy statement NO. 19: Dosimetry in nuclear medicine therapy - Molecular radiotherapy.

The European Council Directive 2013/59/Euratom (BSS Directive) includes optimisation of treatment with radiotherapeutic procedures based on patient dosimetry and verification of the absorbed doses delivered. The present policy statement summarises aspects of three directives relating to the therapeutic use of radiopharmaceuticals and medical devices, and outlines the steps needed for implementation of patient dosimetry for radioactive drugs. To support the transition from administrations of fixed activities to personalised treatments based on patient-specific dosimetry, EFOMP presents a number of recommendations including: increased networking between centres and disciplines to support data collection and development of codes-of-practice; resourcing to support an infrastructure that permits routine patient dosimetry; research funding to support investigation into individualised treatments; inter-disciplinary training and education programmes; and support for investigator led clinical trials. Close collaborations between the medical physicist and responsible practitioner are encouraged to develop a similar pathway as is routine for external beam radiotherapy and brachytherapy. EFOMP's policy is to promote the roles and responsibilities of medical physics throughout Europe in the development of molecular radiotherapy to ensure patient benefit. As the BSS directive is adopted throughout Europe, unprecedented opportunities arise to develop informed treatments that will mitigate the risks of under- or over-treatments.

Quality assurance in clinical dosimetry.

INTRODUCTION: Clinical dosimetry in nuclear medicine is developing fast, with an increasing number of procedures performed for a variety of therapeutic applications. In that context, the advent of CE-marked commercial clinical dosimetry software is a positive signal, as they should, in principle, optimize the workflow and increase robustness. However, they pose the problem of the evaluation of their performances, in terms of accuracy but also ease of use (user-friendliness). AIM: The aim of this presentation is to discuss the various steps required for the evaluation of clinical dosimetry procedures in general, and dosimetry software in particular. MATERIALS AND METHODS: The clinical dosimetry workflow (CDW) is the suite of steps that lead from calibration procedures to the final reporting of the clinical dosimetry procedure. The study of the CDW implemented in various software shows a age variability in the implementation of the steps that constitute the CDW, and the order of their implementation. This can be accepted, however it raises the issue of comparing software that, basically, do not do the same thing, or do things in a different order. RESULTS AND DISCUSSION: The various steps that compose the CDW have to be studied (benchmarked) using specific tools: If assessing calibrations/reconstructions can be made using phantoms filled with radioactive sources, rigid objects are not adapted to the evaluation of registration procedures. Computing anthropomorphic models can be used to verify absorbed dose calculation algorithms (for example using Monte Carlo radiation transport modelling as the gold standard). As can be seen, a range of tools of different type (test objects, models, patient data) must be used - and sometimes developed - to evaluate each step of the CDW. Finally, the end-to-end process must be benchmarked on "real" clinical data, but the price to pay is that the ground truth is not known, thereby limiting these approaches to precision rather than accuracy. CONCLUSION: Nuclear medicine dosimetry quality assurance (QA) is in its infancy. However, procedures already applied in external beam radiotherapy may be easily transposed to nuclear medicine, and it will not take decades until nuclear medicine benefits from sound, reproducible procedures that will increase the robustness of clinical dosimetry procedures.

Normal organ dosimetry for thyroid cancer patients treated with radioiodine as part of the multi-centre multi-national Horizon 2020 MEDIRAD project.

PURPOSE: Dosimetry is rarely performed for the treatment of differentiated thyroid cancer patients with Na[131I]I (radioiodine), and information regarding absorbed doses delivered is limited. Collection of dosimetry data in a multi-centre setting requires standardised quantitative imaging and dosimetry. A multi-national, multi-centre clinical study was performed to assess absorbed doses delivered to normal organs for differentiated thyroid cancer patients treated with Na[131I]I. METHODS: Patients were enrolled in four centres and administered fixed activities of 1.1 or 3.7 GBq of Na[131I]I using rhTSH stimulation or under thyroid hormone withdrawal according to local protocols. Patients were imaged using SPECT(/CT) at variable imaging time-points following standardised acquisition and reconstruction protocols. Whole-body retention data were collected. Dosimetry for normal organs was performed at two dosimetry centres and results collated. RESULTS: One hundred and five patients were recruited. Median absorbed doses per unit administered activity of 0.44, 0.14, 0.05 and 0.16 mGy/MBq were determined for the salivary glands of patients treated at centre 1, 2, 3 and 4, respectively. Median whole-body absorbed doses for 1.1 and 3.7 GBq were 0.05 Gy and 0.16 Gy, respectively. Median whole-body absorbed doses per unit administered activity of 0.04, 0.05, 0.04 and 0.04 mGy/MBq were calculated for centre 1, 2, 3 and 4, respectively. CONCLUSIONS: A wide range of normal organ doses were observed for differentiated thyroid cancer patients treated with Na[131I]I, highlighting the necessity for individualised dosimetry. The results show that data may be collated from multiple centres if minimum standards for the acquisition and dosimetry protocols can be achieved.

A prospective, randomized, phase II study to assess the schemas of retreatment with Lutathera® in patients with new progression of an intestinal, well-differentiated neuroendocrine tumor (ReLUTH).

BACKGROUND: Although neuroendocrine tumors (NET) are classed as rare, they have a high prevalence and their incidence is increasing. Effective treatment with lutetium 17-[177Lu]Lu-oxodotreotide (Lutathera®) is possible in patients with well-differentiated NET, improving progression-free survival (PFS), overall survival (OS), and quality of life (QoL). However, progression does occur. Retreatment with additional Lutathera® cycles is an option to extend PFS and OS. Two retreatment cycles are usually proposed. We aim to compare four versus two Lutathera® retreatment cycles in patients with new progression of a well-differentiated intestinal NET. METHODS: This will be a multicenter, randomized, controlled, open-label, phase II study in France (ReLUTH). The aim is to evaluate the efficacy of retreatment with Lutathera® in patients with progressive intestinal NET (determined by somatostatin-receptor positive imaging) after previous treatment with two cycles of Lutathera®. Before randomization, all patients will have already received two Lutathera® retreatment cycles (7.4 GBq infusion each, 8 weeks apart). A total of 146 patients will be randomized (1:1) to two additional cycles of Lutathera® (7.4 GBq infusion each, separated by 8 weeks) or to no treatment (active surveillance). PRIMARY OBJECTIVE: efficacy of two additional Lutathera® retreatment cycles compared to active surveillance over 6 months. PRIMARY ENDPOINT: disease control rate at 6 months from randomization (defined as Complete Response, Partial Response, and Stable Disease in the Response Evaluation Criteria In Solid Tumours) with an evaluation every 2 months. A secondary objective will be the safety, as well as the PFS, OS, and QoL. It is expected that the efficacy of retreatment will increase after two additional Lutathera® cycles, with no increased safety concerns. DISCUSSION: Our prospective, randomized controlled study may lead to new recommendations for the use of Lutathera® in patients with intestinal progressive NET, and should confirm that four cycles will be more effective than two, with limited adverse impact on safety. Four Lutathera® treatment cycles have the potential to prolong life and improve quality of life in patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04954820.

Therapeutic efficacy of 166Holmium siloxane in microbrachytherapy of induced glioblastoma in minipig tumor model.

Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a preclinical experiment to evaluate therapeutic efficacy of 166Ho microparticle suspension administered by microbrachytherapy on a minipig glioblastoma model. Twelve minipigs were divided in 3 groups. Minipigs had injections into the tumor, containing microparticle suspensions of either 166Ho (group 1; n = 6) or 165Ho (group 2; n = 3) and control group (group 3; n = 3). The survival time from treatment to euthanasia was 66 days with a good state of health of all minipigs in group 1. The median survival time from treatment to tumor related death were 8.6 and 7.3 days in groups 2 and control, respectively. Statistically, the prolonged life of group 1 was significantly different from the two other groups (p < 0.01), and no significant difference was observed between group 2 and control (p=0.09). Our trial on the therapeutic effect of the 166Ho microparticle demonstrated an excellent efficacy in tumor control. The histological and immunohistochemical analysis showed that the efficacy was related to a severe 166Ho induced necrosis combined with an immune response due to the presence of the radioactive microparticles inside the tumors. The absence of reflux following the injections confirms the safety of the injection device.

Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals.

BACKGROUND: The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products. MAIN BODY: To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as "non-clinical" or "preclinical" are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed. CONCLUSION: This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way.

Modelling SPECT auto-contouring acquisitions for 177Lu & 131I molecular radiotherapy using new developments in Geant4/GATE.

PURPOSE: Monte Carlo modelling of SPECT imaging in Molecular Radiotherapy can improve activity quantification. Until now, SPECT modelling with GATE only considered circular orbit (CO) acquisitions. This cannot reproduce auto-contour acquisitions, where the detector head moves close to the patient to improve image resolution. The aim of this work is to develop and validate an auto-contouring step-and-shoot acquisition mode for GATE SPECT modelling. METHODS: 177Lu and 131I SPECT experimental acquisitions performed on a Siemens Symbia T2 and GE Discovery 670 gamma camera, respectively, were modelled. SPECT projections were obtained for a cylindrical Jaszczak phantom and a lung and spine phantom. Detector head parameters (radial positions and acquisition angles) were extracted from the experimental projections to model the non-circular orbit (NCO) detector motion. The gamma camera model was validated against the experimental projections obtained with the cylindrical Jaszczak (177Lu) and lung and spine phantom (131I). Then, 177Lu and 131I CO and NCO SPECT projections were simulated to validate the impact of explicit NCO modelling on simulated projections. RESULTS: Experimental and simulated SPECT images were compared using the gamma index, and were in good agreement with gamma index passing rate (GIPR) and gammaavg of 96.27%, 0.242 (177Lu) and 92.89%, 0.36 (131I). Then, simulated 177Lu and 131I CO and NCO SPECT projections were compared. The GIPR, gammaavg between the two gamma camera motions was 99.85%, 0.108 for 177Lu and 75.58%, 0.6 for 131I. CONCLUSION: This work thereby justifies the need for auto-contouring modelling for isotopes with high septal penetration.

From the target cell theory to a more integrated view of radiobiology in Targeted radionuclide therapy: The Montpellier group's experience.

Targeted radionuclide therapy (TRT) is used to treat disseminated or metastatic tumours in which conventional external beam radiotherapy (EBRT) would have unacceptable side effects. Unlike EBRT, TRT delivers low doses at a continuous low dose rate. In EBRT, the effect increases progressively with the dose rate, and biological effects (tumour control and normal tissue damage) are related to the dose according to a sigmoid curve model. This model is part of the so-called quantitative radiobiology that is mostly based on the target cell theory, according to which cell death is due to (lethal) radiation hits to vital cellular targets. This model was developed for EBRT, but was adapted to low dose-rate situations by including a parameter that reflects the time needed to repair tissue damage. However, a growing body of evidence indicates that the model should take into account also the biological effects, which are due to intercellular communications (bystander effects) and amplify the effects of radiation, as well as the immune system. Moreover, extranuclear targets must be considered, although induced intracellular and intercellular signalling pathways may ultimately result in DNA damage. It is likely that bystander effects and immune response always contribute to the overall response to TRT at different levels, and that dose and dose rate are key parameters in controlling their real contribution. We hypothesize that the dose rate is the key determinant in the balance between the physical and DNA-centred response on one side, and the biological response that integrates all subcellular compartments and intercellular signalling pathways on the other side.

Overview of commercial treatment planning systems for targeted radionuclide therapy.

INTRODUCTION: Targeted Radionuclide Therapy (TRT) is a branch of cancer medicine dealing with the therapeutic use of radioisotopes associated with biological vectors accumulating in the tumors/targets, indicated as Molecular Radiotherapy (MRT), or directly injected into the arteries that supply blood to liver tumour vasculature, indicated as Selective RT (SRT). The aim of this work is to offer a panoramic view on the increasing number of commercially-available TRT treatment planning systems (TPSs). MATERIALS AND METHODS: A questionnaire was sent to manufacturers' representatives. Academic software were not considered. Questions were grouped as follows: general information, clinical workflow, calibration procedure, image processing/reconstruction, image registration and segmentation tools, time-activity curve (TAC) fitting and absorbed dose calculation. RESULTS: All software reported have CE-marking. TPSs were divided between SRT-dedicated software [4] and MRT [5] dosimetry software. In SRT, since no kinetic process is involved, absorbed dose calculation does not require TAC fitting, and image registration is not fully developed in all TPS. All software requires a radionuclide-specific calibration. In SRT, a relative image calibration can be obtained by scaling the counts to a known activity. Automated VOI contouring and rigid/deformable propagation between different acquisitions time-points is implemented in most TPSs, although DICOM export is rare. Different TAC fits are available depending on the number of time-points. Voxel S-value and Local deposition methods are the most frequent dosimetric approaches; dose-voxel kernel convolution and semi-Monte Carlo method are also available. CONCLUSIONS: Available TPSs allows performing personalized dosimetry in clinical practice. Individual variations in methodology/algorithms must be considered in the standardisation/harmonization processes.

Whole body planar and 3D quantitative imaging after 177Lu-DOTATATE on CZT SPECT/CT device with MEHRS collimator. First report.

Lutetium-177 (177Lu)-based post-therapeutic imaging allows visualization of treated lesions andabsorbed dose measurement. There is an increasing number of cadmium-zinc-telluride (CZT) gamma-cameras in nuclear medicine departments but until now these devices were not adapted to the medium-energy emission of 177Lu photons. We present here in the first reported images acquired with a new collimator designed for CZT gamma-camera compared to a conventional sodium iodide (NaI) (Tl) gamma-camera. Post-therapeutic 177Lu-DOTATATE imaging on a CZT device with a medium energy high resolution (MEHRS)-collimator are promising and support the widespread of both 177Lu-based peptide-receptor radionuclide therapy (PRRT) and CZT gamma-cameras.

Technical note: GAMMORA, a free, open-source, and validated GATE-based model for Monte-Carlo simulations of the Varian TrueBeam.

PURPOSE: Monte Carlo (MC) is the reference computation method for medical physics. In radiotherapy, MC computations are necessary for some issues (such as assessing figures of merit, double checks, and dose conversions). A tool based on GATE is proposed to easily create full MC simulations of the Varian TrueBeam STx. METHODS: GAMMORA is a package that contains photon phase spaces as a pre-trained generative adversarial network (GAN) and the TrueBeam's full geometry. It allows users to easily create MC simulations for simple or complex radiotherapy plans such as VMAT. To validate the model, the characteristics of generated photons are first compared to those provided by Varian (IAEA format). Simulated data are also compared to measurements in water and heterogeneous media. Simulations of 8 SBRT plans are compared to measurements (in a phantom). Two examples of applications (a second check and interplay effect assessment) are presented. RESULTS: The simulated photons generated by the GAN have the same characteristics (energy, position, and direction) as the IAEA data. Computed dose distributions of simple cases (in water) and complex plans delivered in a phantom are compared to measurements, and the Gamma index (3%/3mm) was always superior to 98%. The feasibility of both clinical applications is shown. CONCLUSIONS: This model is now shared as a free and open-source tool that generates radiotherapy MC simulations. It has been validated and used for five years. Several applications can be envisaged for research and clinical purposes.

A study of the interplay effect in radiation therapy using a Monte-Carlo model.

PURPOSE: In modulated radiotherapy, breathing motion can lead to Interplay (IE) and Blurring (BE) effects that can modify the delivered dose. The aim of this work is to present the implementation, the validation and the use of an open-source Monte-Carlo (MC) model that computes the delivered dose including these motion effects. METHODS: The MC model of the Varian TrueBeam was implemented using GATE. The dose delivered by different modulated plans is computed for several breathing patterns. A validation of these MC predictions is achieved by a comparison with measurements performed using a dedicated programmable motion platform, carrying a quality assurance phantom. A specific methodology was used to separate the IE and the BE. The influence of different motion parameters (period, amplitude, shape) and plan parameters (volume margin, dose per fraction) was also analyzed. RESULTS: The MC model was validated against measurement performed with motion with a mean 3D global gamma index pass rate of 97.5% (3%/3 mm). A significant correlation is found between the IE and the period and the antero-posterior amplitude of the motion but not between the IE and the CTV margin or the shape of motion. The results showed that the IE increases D2% and decreases the D98% of CTV with mean values of +6.9% and -3.3% respectively. CONCLUSIONS: We validated the feasibility to assess the IE using a MC model. We found that the most important parameter is the number of breathing cycles that must be greater than 20 for one arc to limit the IE.

Generation of clinical 177Lu SPECT/CT images based on Monte Carlo simulation with GATE.

PURPOSE: Patient-specific dosimetry in MRT relies on quantitative imaging, pharmacokinetic assessment and absorbed dose calculation. The DosiTest project was initiated to evaluate the uncertainties associated with each step of the clinical dosimetry workflow through a virtual multicentric clinical trial. This work presents the generation of simulated clinical SPECT datasets based on GATE Monte Carlo modelling with its corresponding experimental CT image, which can subsequently be processed by commercial image workstations. METHODS: This study considers a therapy cycle of 6.85 GBq 177Lu-labelled DOTATATE derived from an IAEA-Coordinated Research Project (E23005) on "Dosimetry in Radiopharmaceutical therapy for personalised patient treatment". Patient images were acquired on a GE Infinia-Hawkeye 4 gamma camera using a medium energy (ME) collimator. Simulated SPECT projections were generated based on experimental time points and validated against experimental SPECT projections using flattened profiles and gamma index. The simulated projections were then incorporated into the patient SPECT/CT DICOM envelopes for processing and their reconstruction within a commercial image workstation. RESULTS: Gamma index passing rate (2% - 1 pixel criteria) between 95 and 98% and average gamma between 0.28 and 0.35 among different time points revealed high similarity between simulated and experimental images. Image reconstruction of the simulated projections was successful on HERMES and Xeleris workstations, a major step forward for the initiation of a multicentric virtual clinical dosimetry trial based on simulated SPECT/CT images. CONCLUSIONS: Realistic 177Lu patient SPECT projections were generated in GATE. These modelled datasets will be circulated to different clinical departments to perform dosimetry in order to assess the uncertainties in the entire dosimetric chain.

Advanced Monte Carlo simulations of emission tomography imaging systems with GATE.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model.

Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression. METHODS: Pharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (µPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans. RESULTS: Organ distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 µSv/MBq. CONCLUSION: The predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.