Développement d’un imageur gamma ambulatoire pour le contrôle de la dose en radiothérapie interne vectorisée

Targeted radionuclide therapy is still a developing area among the different treatment modalities against cancer. However, its range of applications is rapidly expanding thanks to the emergence of new radiopharmaceuticals labeled with beta or alpha emitters (peptides, ²²³ Ra alpha-therapy, ²²¹ As alpha- immunotherapy, ...) (Ersahin 2011). In that context, the large heterogeneity of absorbed doses and the range of effects observed, both in terms of toxicity and response, demonstrate that individualized patient dosimetry is essential to optimize this therapy (Strigari 2011). In clinical practice, patient-specific dosimetry of tumors and organs-at-risk (liver, kidney, ...) is image-based and rely on the quantification of radio- pharmaceutical uptake as a function of time. These images can be obtained from either a pre-therapy tracer study or from a previous therapy procedure. The detection constraints imposed by the treatment protocols are very different from those associated with diagnostic imaging. (Flux 2011 Konijnenberg 2011). Thus, conventional gamma cameras are not suited for detecting high activity of gamma emitters with energy below 100 keV (²²³ Ra) or greater than 300 keV (¹³¹ I, ⁹⁰Y ). Moreover, high activities of the injected tracer typically require isolation of the patient, making the use of standard imaging devices difficult. Finally, the availability of these devices is incompatible with an accurate temporal sampling of the kinetics of the tracer, which is a key parameter for the quantification of the absorbed doses. The objective of my thesis was precisely to propose new instrumental and methodological approaches aiming to strengthen the control of the dose released to patients during molecular radiotherapy. This is achieved by reducing the uncertainties associated to activity quantification (and therefore to the absorbed dose calculation) through the use of a compact and highly optimized imaging system. Specifically, the work consisted in the development and optimization of a miniaturized, high-resolution mobile gamma camera specifically designed to improve the individual quantitative assessment of the heterogeneous distribution and biokinetics of the radiotracer before and after treatment administration. The study was focused on the treatment of benign and malign thyroid disease with ¹³¹ I. The first prototype of the mobile camera, with a field of view of 5x5 cm², consists of a high-energy parallel- hole collimator, optimized with Monte Carlo simulation and made with 3D printing, coupled to a 6 mm thick continuous CeBr3 scintillator readout by a recent and well-suited technology based on arrays of Silicon Pho- tomultiplier (SiPMs) detectors. Its intrinsic properties, in term of energy and spatial response, have been tested with collimated point source of ⁵⁷Co and ¹³³Ba. The first feasibility prototype has been then calibrated with a line and five cylindrical sources filled with ¹³¹ I. The system calibration leads to an overall spatial resolution of (3.14±0.03) mm at a distance of 5 cm and a sensitivity that decreases with distance and slightly changes with source size. An average sensitivity of (1.23±0.01) cps/MBq has been found at 5 cm. In order to test the quantification capability of the camera, the first preclinical planar studies involved the use of different 3D-printed thyroid phantoms filled with ¹³¹ I, with and without nodules. Although corresponding to a relatively ideal, but realistic, clinical situation (no superimposition of background activity), the optimized imaging features of the camera leads to very promising results, with activity recovery factors that deviate of around 2% from the unity.La thérapie interne par radionucléides est encore aujourd’hui un domaine peu exploité parmi les différentes modalités de traitement contre le cancer. Son spectre d’applications est toutefois en pleine évolution grâce notamment à l'apparition de nouveaux radiopharmaceutiques émetteurs beta ou alpha (peptides, alpha-thérapie ²²³ Ra, alpha-immunothérapie ²²¹ As,...) (Ersahin 2011). Dans ce contexte, la grande hétérogénéité des doses délivrées et des effets observés, à la fois en terme de toxicité et de réponse, démontrent qu'une dosimétrie personnalisée est essentielle pour optimiser le traitement (Strigari 2011). En pratique clinique, la dosimétrie de la tumeur et des organes à risque (foie, rein, ...) repose sur l’image de la biodistribution et de la cinétique précise du radiopharmaceutique chez chaque patient. Ces images peuvent être réalisées avec un traceur pré-thérapeutique pour planifier le traitement ou après celui-ci, afin de corréler directement les effets observés aux doses délivrées de manière à optimiser le protocole (activité maximum à injecter, intervalle entre les injections). Les contraintes de détection imposées par les protocoles de traitement sont très différentes de celles associées à un examen diagnostique (Flux 2011, Konijnenberg 2011). Les gamma-caméras conventionnelles ne sont ainsi pas adaptées à la détection de fortes activités de rayonnements gamma d'énergies inférieures à 100 keV (²²³ Ra) ou supérieures à 300 keV (¹³¹I, ⁹⁰Y). D’autre part, les fortes activités des traceurs injectés exigent généralement que le patient reste isolé, ce qui le rend donc plus difficilement accessible par les techniques d’imagerie standard. Enfin, la disponibilité de ces systèmes est incompatible avec un échantillonnage temporel précis de la cinétique du traceur, qui joue un rôle très important dans la quantification des doses absorbées. L'objectif de ma thèse était de proposer de nouvelles approches instrumentales visant à renforcer le contrôle de la dose délivrée aux patients lors d'un traitement de radiothérapie moléculaire. Ceci est réalisé en réduisant les incertitudes associées à la quantification de l'activité (et donc au calcul de la dose absorbée) grâce à l'utilisation d'un système d'imagerie compact et hautement optimisé. Il consistait à mettre au point et à optimiser une gamma-caméra mobile miniaturisée à haute résolution spécialement conçue pour améliorer l'évaluation quantitative individuelle de la distribution hétérogène et de la bio-cinétique du radiotraceur avant et après administration du traitement. L'étude était axée sur le traitement des maladies bénignes et malignes de la thyroïde à l'aide de l'¹³¹ I. Le premier prototype de la caméra, avec un champ de vue de 5x5 cm² , consiste en un collimateur à trous parallèles à haute énergie, réalisé en impression 3D et optimisé par simulations Monte Carlo, couplé à un scintillateur inorganique continu, lu par une technologie récente basée sur des matrices de photomultiplicateurs au silicium (SiPM). Ses propriétés intrinsèques, en termes d'énergie et de réponse spatiale, ont été testées avec des sources ponctuelles de ⁵⁷ Co et ¹³³ Ba. Le premier prototype de la caméra a été calibré avec de l'¹³¹ I. La calibration du système conduit à une résolution spatiale globale de (3.14±0.03) mm et à une sensibilité moyenne de (1.23±0.01) cps/MBq, le deux à 5 cm de distance. Nous avons effectué les premières études précliniques avec l'utilisation de différents fantômes thyroïdiens imprimés en 3D, avec et sans nodules, remplis de ¹³¹ I. Des résultats très prometteurs ont été atteints (valeurs de RC proches de l’unité), qui mettent en évidence ses performances adaptées à une quantification précise dans un contexte clinique assez réaliste

Optimization of scintillator–reflector optical interfaces for the LUT Davis model

PurposeDesigning and optimizing scintillator-based gamma detector using Monte Carlo simulation is of great importance in nuclear medicine and high energy physics. In scintillation detectors, understanding the light transport in the scintillator and the light collection by the photodetector plays a crucial role in achieving high performance. Thus, accurately modeling them is critical.MethodsIn previous works, we developed a model to compute crystal reflectance from the crystal 3D surface measurement and store it in look-up tables to be used in the Monte Carlo simulation software GATE. The relative light output comparison showed excellent agreement between simulations and experiments for both polished and rough surfaces in several configurations, that is, without and with reflector. However, when comparing them at the irradiation depth closest to the photodetector face, rough crystals with a reflector overestimated the predicted light output. Investigating the cause of this overestimation, we optimized the LUT algorithm to improve the reflectance computation accuracy, especially for rough surfaces. However, optical Monte Carlo simulations carried out with these newly generated LUTs still overestimate the light output. Based on previous observations, one probable cause is the erroneous assumption of perfect couplings between the reflector and crystal and between the crystal and photodetector, which likely results in an important overestimation of the light output compared to experimental values. In practice, several factors could degrade it. Here, we investigated possible suboptimal optical experimental configurations that could lead to a degraded light collection when using Teflon or ESR reflectors coupled to the crystal with air or grease. We generated look-up tables with a mixture of air and grease and showed the effect of three possible sources of light loss: the presence of a small gap between the crystal and the reflector edges close to the photodetector face, the infiltration of grease in the crystal-reflector coupling, and the presence of inhomogeneities in the photodetector-crystal interface.ResultsThe strongest effect is linked to the presence of a small gap of grease between the edges of the reflector material and the crystal (light loss of 10%-12% for 0.2 mm gap). The optical grease infiltrating the crystal-reflector air coupling decreases the light output, depending on the infiltration's extent and the amount of grease infiltrated. Five percent of air in the crystal-photodetector coupling can cause a light output decrease of 2% to 4%. The individual and combined effect of these advanced models can explain the discrepancy of the relative light output obtained with ESR in simulations and experiments. With Teflon, the study indicates that the light output loss strongly depends on the reflectance deterioration caused by grease absorption.ConclusionsOur results indicate that when studying scintillation detector performance with different finishes, performing simulations in ideal coupling conditions can lead to light output overestimation. To perform an accurate light output comparison and ultimately have a reliable detector performance estimation, all potential sources of practical limitations must be carefully considered. To broadly enable high-fidelity modeling, we developed an interface for users to compute their own LUTs, using their surface, scintillator, and reflector characteristics

Integration of polarization in the LUTDavis model for optical Monte Carlo simulation in radiation detectors

ObjectiveCerenkov photons have distinctive features from scintillation photons. Among them is their polarization: their electric field is always perpendicular to the direction of propagation of light and parallel to the plane of incidence. Scintillation photons are instead considered unpolarized.ApproachThis study aims at understanding and optimizing the reflectance of polarized Cerenkov photons for optical Monte Carlo simulation of scintillation detectors with Geant4/GATE. First, the Cerenkov emission spectrum and polarization were implemented in the previously developed look-up-table Davis model of crystal reflectance. Next, we modified Geant4/GATE source code to account for scintillation and Cerenkov photons LUTs simultaneously. Then, we performed optical Monte Carlo simulations in BGO using GATE to show the effect of Cerenkov features on the photons' momentum at the photodetector face, using two surface finishes, with and without reflector.Main resultsIn this work, we describe the new features added to the algorithm and GATE. We showed that Cerenkov characteristics affect their probability to be reflected/refracted and thus their travel path within a material.SignificanceWe showed the importance of accounting for accurate Cerenkov photons reflectance while performing advanced optical Monte Carlo simulations

DataSheet1_Effect of crystal-photodetector interface extraction efficiency on Cerenkov photons’ detection time.docx

Using Cerenkov photons to improve detector timing resolution in time-of-flight positron emission tomography scanners is promising since they constitute most of the signal rising edge. The main challenge in using Cerenkov light is its low yield per photoelectric interaction, which requires optimizing their complex optical transport in the detector. Monte Carlo simulations unlock information unavailable through benchtop measurements and help better understand the Cerenkov photon behavior. Although the first Cerenkov photons are emitted forward, part of the early triggering signal is lost due to poor light extraction at the crystal-photodetector interface. In addition, the electron path in the crystal, that determines the Cerenkov photon direction, is tortuous due to multiple scattering, causing the Cerenkov photons emitted after a few scatters to no longer be forward-directed. In this context, the transit time spread in the crystal, highly dependent on the detector geometry, plays a crucial role in the photon detection time. In this work, we performed optical simulations in bismuth germanium oxide using 511 keV gamma with GATE to investigate the optical photons extraction when modifying the index of refraction at the crystal-photodetector interface and the crystal aspect ratio. The mean detection time of the first, second, and third detected optical and Cerenkov photon separately was studied as a function of the total number of Cerenkov detected per event. For each configuration, we calculated the expected mean detection time using the probability of detection. Thinner crystals led to lower expected detection times due to the reduced transit time in the crystal. Reducing the refractive index discontinuity at the crystal-photodetector interface decreased all configurations expected mean detection time values. We showed that it not only improves the optical photons (scintillation and Cerenkov) detection efficiency at the photodetector face but directly ameliorates the probability of detecting the fastest one, reducing the effect of thicker materials and of losing the first detected photon information, both crucial to reduce the detector timing resolution. Thanks to their prompt emission and directionality at emission, Cerenkov photons represent the first detected optical photon in most configurations but increasing their detection efficiency is crucial to detect the fastest one.</p

DataSheet7_Effect of crystal-photodetector interface extraction efficiency on Cerenkov photons’ detection time.docx

Using Cerenkov photons to improve detector timing resolution in time-of-flight positron emission tomography scanners is promising since they constitute most of the signal rising edge. The main challenge in using Cerenkov light is its low yield per photoelectric interaction, which requires optimizing their complex optical transport in the detector. Monte Carlo simulations unlock information unavailable through benchtop measurements and help better understand the Cerenkov photon behavior. Although the first Cerenkov photons are emitted forward, part of the early triggering signal is lost due to poor light extraction at the crystal-photodetector interface. In addition, the electron path in the crystal, that determines the Cerenkov photon direction, is tortuous due to multiple scattering, causing the Cerenkov photons emitted after a few scatters to no longer be forward-directed. In this context, the transit time spread in the crystal, highly dependent on the detector geometry, plays a crucial role in the photon detection time. In this work, we performed optical simulations in bismuth germanium oxide using 511 keV gamma with GATE to investigate the optical photons extraction when modifying the index of refraction at the crystal-photodetector interface and the crystal aspect ratio. The mean detection time of the first, second, and third detected optical and Cerenkov photon separately was studied as a function of the total number of Cerenkov detected per event. For each configuration, we calculated the expected mean detection time using the probability of detection. Thinner crystals led to lower expected detection times due to the reduced transit time in the crystal. Reducing the refractive index discontinuity at the crystal-photodetector interface decreased all configurations expected mean detection time values. We showed that it not only improves the optical photons (scintillation and Cerenkov) detection efficiency at the photodetector face but directly ameliorates the probability of detecting the fastest one, reducing the effect of thicker materials and of losing the first detected photon information, both crucial to reduce the detector timing resolution. Thanks to their prompt emission and directionality at emission, Cerenkov photons represent the first detected optical photon in most configurations but increasing their detection efficiency is crucial to detect the fastest one.</p

Technical Note: Standalone application to generate custom reflectance Look‐Up Table for advanced optical Monte Carlo simulation in GATE/Geant4

PurposeThe need for high-fidelity modeling of radiation detectors to perform reliable detector performance optimization using Monte Carlo simulations requires to accurately simulate the light transport in the scintillator and the light collection by the photodetector. In this work, we implement our well-validated crystal reflectance model computed from three-dimensional (3D) crystal surface measurement in a standalone open-source application to allow researchers to generate fully customized crystal reflectance look-up-tables (LUTs) to be used in optical Monte Carlo simulation.MethodsThe LUTDavisModel application can be installed in a few minutes on Windows, macOS, and Linux, using 26&nbsp;MB of space. MATLAB Runtime is required and is automatically installed with the application. The core algorithm has been previously validated experimentally and implemented in GATE v8.0. The standalone is divided into five panels, each of which performing a specific task: generate LUTs from a combination of surface type, scintillator, and coupling medium available in the database (such as LSO or BGO) or custom; compute LUTs with the reflectors available and custom coupling thickness; create a mixture of coupling media to account for possible defects in the optical coupling; plot precomputed LUTs for visual comparison. Tooltips and errors/warnings facilitate the navigation. The reported computational times were obtained with an Intel Core i7 MacBook Pro.ResultsLUTs can be generated with computational time ranging from a few minutes to several hours depending on the selected surface, sampling, and computational power. A longer time is needed when using rough surfaces and thick coupling media (hundreds of μm ) due to increased photon tracking.ConclusionsWe developed a user-friendly standalone application to generate LUTs that can be used inside GATE Monte Carlo simulations. It can be easily downloaded, installed, and used. Future optimizations will expand the database, decrease the computational time through greater parallelization, and include the generation of LUTs to study Cerenkov photons transport

DataSheet2_Effect of crystal-photodetector interface extraction efficiency on Cerenkov photons’ detection time.docx

Using Cerenkov photons to improve detector timing resolution in time-of-flight positron emission tomography scanners is promising since they constitute most of the signal rising edge. The main challenge in using Cerenkov light is its low yield per photoelectric interaction, which requires optimizing their complex optical transport in the detector. Monte Carlo simulations unlock information unavailable through benchtop measurements and help better understand the Cerenkov photon behavior. Although the first Cerenkov photons are emitted forward, part of the early triggering signal is lost due to poor light extraction at the crystal-photodetector interface. In addition, the electron path in the crystal, that determines the Cerenkov photon direction, is tortuous due to multiple scattering, causing the Cerenkov photons emitted after a few scatters to no longer be forward-directed. In this context, the transit time spread in the crystal, highly dependent on the detector geometry, plays a crucial role in the photon detection time. In this work, we performed optical simulations in bismuth germanium oxide using 511 keV gamma with GATE to investigate the optical photons extraction when modifying the index of refraction at the crystal-photodetector interface and the crystal aspect ratio. The mean detection time of the first, second, and third detected optical and Cerenkov photon separately was studied as a function of the total number of Cerenkov detected per event. For each configuration, we calculated the expected mean detection time using the probability of detection. Thinner crystals led to lower expected detection times due to the reduced transit time in the crystal. Reducing the refractive index discontinuity at the crystal-photodetector interface decreased all configurations expected mean detection time values. We showed that it not only improves the optical photons (scintillation and Cerenkov) detection efficiency at the photodetector face but directly ameliorates the probability of detecting the fastest one, reducing the effect of thicker materials and of losing the first detected photon information, both crucial to reduce the detector timing resolution. Thanks to their prompt emission and directionality at emission, Cerenkov photons represent the first detected optical photon in most configurations but increasing their detection efficiency is crucial to detect the fastest one.</p