L’imagerie proton est étudiée comme alternative à la tomodensitométrie X pour la planification de traitement en hadronthérapie. En obtenant directement les pouvoirs d’arrêt relatifs des tissus, l’incertitude sur le parcours des particules pourrait être réduite. Un scanner à protons est constitué d’un calorimètre ou d’un détecteur de parcours afin d’obtenir l’information sur l’énergie déposée par chaque proton dans l’objet imagé et de deux ensembles de trajectographes enregistrant la position et direction de chaque particule en amont et en aval de l’objet. Ce travail concerne l’étude des données d’un scanner à protons et l’utilisation possible de toutes les informations enregistrées. Une étude de reconstruction d’image a permis de montrer que les informations sur le taux de transmission et sur la déviation de chaque particule peuvent être utilisées pour produire des images aux propriétés visuelles intéressantes pour le diagnostic. La preuve de concept de la possibilité d’une imagerie quantitative utilisant ces informations est présentée. Ces résultats sont une première étape vers l’imagerie proton utilisant toutes les données enregistrées. / Proton computed tomography is being studied as an alternative to X-ray CT imaging for charged particle therapy treatment planning. By directly mapping the relative stopping power of the tissues, the uncertainty on the range of the particles could be reduced. A proton scanner consists in a calorimeter or range-meter to obtain the information on the energy lost by each proton in the object, as well as two sets of tracking planes to record the position and direction of each particle upstream and downstream from the object. This work concerns the study of the outputs of a proton scanner and the possible use of all the recorded information. A reconstruction study made it possible to show that the information on the transmission rate and on the scattering of each particle can be used to produce images with visual properties that could be of interest for diagnostics. The proof of concept of the possibility of quantitative imaging using this information is also put forward. These results are the first step towards a clinical use of proton imaging with all the recorded data.

Malgré de récentes avancées, les traitements par radiothérapie (RT) demeurent insatisfaisants : la tolérance des tissus sains aux rayonnements limite la délivrance de fortes doses (potentiellement curatives) à la tumeur. Pour remédier à ce problème, de nouvelles approches basées sur des modes de dépôt de dose innovants sont aujourd’hui à l’étude. Parmi ces approches, la technique synchrotron “Minibeam Radiation Therapy” (MBRT) a démontré sa capacité à élever la résistance des tissus sains aux rayonnements, ainsi qu’à induire un important retard de croissance tumorale. La MBRT combine des faisceaux submillimétriques à un fractionnement spatial de la dose. Dans ce contexte, l’alliance de la balistique plus avantageuse des particules chargées (et leur sélectivité biologique) à la préservation des tissus sains observée en MBRT permettrait de préserver d’avantage les tissus sains. Cette stratégie innovante a été explorée durant ce travail de thèse. Deux voies ont notamment été étudiées: la MBRT par faisceaux de protons (pMBRT), et d’ions très lourds. Premièrement, la preuve de concept expérimentale de la pMBRT a été réalisée dans un centre clinique (Institut Curie, Centre de Protonthérapie d’Orsay). De plus, l'évaluation de potentielles optimisations de la pMBRT, à la fois en terme de configuration d’irradiation et de génération des minifaisceaux, a été menée dans une étude Monte Carlo (MC). Dans la seconde partie de ce travail, un nouvel usage potentiel des ions très lourds (néon et plus lourds) en radiothérapie a été évalué dans une étude MC. Les combiner à un fractionnement spatial permettrait de tirer profit de leur efficacité dans le traitement de tumeurs radiorésistantes (hypoxiques), un des principaux défis de la RT, tout en minimisant leurs effets secondaires. Les résultats obtenus au terme de ce travail sont favorables à une exploration approfondie de ces deux approches innovantes. Les données dosimétriques compilées dans ce manuscrit serviront à guider prochaines les expérimentations biologiques. / Despite recent breakthroughs, radiotherapy (RT) treatments remain unsatisfactory : the tolerance of normal tissues to radiations still limits the possibility of delivering high (potentially curative) doses in the tumour. To overcome these difficulties, new RT approaches using distinct dose delivery methods are being explored. Among them, the synchrotron minibeam radiation therapy (MBRT) technique has been shown to lead to a remarkable normal tissue resistance to very high doses, and a significant tumour growth delay. MBRT allies sub-millimetric beams to a spatial fractionation of the dose. The combination of the more selective energy deposition of charged particles (and their biological selectivity) to the well-established normal tissue sparing of MBRT could lead to a further gain in normal tissue sparing. This innovative strategy was explored in this Ph.D. thesis. In particular, two new avenues were studied: proton MBRT (pMBRT) and very heavy ion MBRT. First, the experimental proof of concept of pMBRT was performed at a clinical facility (Institut Curie, Orsay, France). In addition, pMBRT setup and minibeam generation were optimised by means of Monte Carlo (MC) simulations. In the second part of this work, a potential renewed use of very heavy ions (neon and heavier) for therapy was evaluated in a MC study. Combining such ions to a spatial fractionation could allow profiting from their high efficiency in the treatment of hypoxic radioresistant tumours, one of the main challenges in RT, while reducing at maximum their side effects. The promising results obtained in this thesis support further explorations of these two novel avenues. The dosimetry knowledge acquired will serve to guide the biological experiments.

Proton radiotherapy is a cancer treatment which has the potential to offer greater cure rates and/or fewer serious side effects than conventional radiotherapy. Its availability in the UK is currently limited to a single low-energy fixed beamline for the treatment of ocular tumours, but a number of facilities designed to treat deep-seated tumours are in development. This thesis focusses on the quantitative use of x-ray computed tomography (CT) images in planning proton radiotherapy treatments. It arrives at several recommendations that can be used to inform clinical protocols for the acquisition of planning scans, and their subsequent use in treatment planning systems. The primary tool developed is a software CT scanner, which simulates images of an anthropomorphic virtual phantom, informed by measurements taken on a clinical scanner. The software is used to investigate the accuracy of the stoichiometric method for calibrating CT image pixel values to proton stopping power, with particular attention paid to the impact of beam hardening and photon starvation artefacts. The strength of the method adopted is in allowing comparison between CT-estimated and exactly-calculated proton stopping powers derived from the same physical data (specified in the phantom), leading to results that are difficult to obtain otherwise. A number of variations of the stoichiometric method are examined, identifying the best-performing calibration phantom and CT tube voltage (kVp). Improvements in accuracy are observed when using a second-pass beam hardening correction algorithm. Also presented is a method for identifying the proton paths where stopping power uncertainties are likely to be greatest. Estimates of the proton range uncertainties caused by CT artefacts and calibration errors are obtained for a range of realistic clinical scenarios. The current practice of including planning margins equivalent to 3.5% of the range is found to ensure coverage in all but the very worst of cases. Results herein suggest margins could be reduced to <2% if the best-performing protocol is followed; however, an analysis specific to the CT scanner and treatment site in question should be carried out before such a change is made in the clinic.

Au cours du traitement d'une tumeur avec des ions légers, la position du pic de Bragg doit être connue avec précision. Une fraction importante des ions incidents subissent des collisions nucléaires avec les noyaux cibles conduisant à l'émission de particules promptes qui peuvent être porteuses d'informations sur le parcours des ions. Ce travail, qui se concentre sur les gamma prompts, montre que le rendement en profondeur de ces émissions est fortement corrélé au parcours des ions et que les taux de comptage mesurés permettent d'envisager un système d'imagerie réaliste, fonctionnant en temps réel. Dans ce but, nous avons réalisé des expériences au GANIL et au GSI avec un détecteur collimaté placé perpendiculairement à l'axe du faisceau et la technique du temps de vol a été utilisée pour réduire le bruit de fond induit par les neutrons et les particules chargées. Des simulations Geant4 ont été réalisées pour concevoir le dispositif expérimental et interpréter les données. Un accord qualitatif entre les simulations et l'expérience est observé pour la quantité d'énergie déposée dans le détecteur et pour la forme du spectre de temps de vol. Cependant, des divergences apparaissent pour le rendement de gamma prompts et la distribution en profondeur des gamma détectés. Ces divergences sont discutées, principalement en termes de modèles de physique nucléaire qui doivent être améliorés. Après avoir sélectionné les modèles physiques offrant les simulations les plus en accord avec les mesures, des études concernant les lieux d'émissions des gamma prompts et l'influence de la diffusion dans la cible ont été réalisés afin de déterminer l'impact sur la corrélation avec le parcours des ions / During the treatment of a tumor with light ions, the Bragg peak location must be accurately known. A significant fraction of the incident ions undergo nuclear collisions with the target nuclei leading to the prompt emission of particles which may carry information on the ion path. This work, which focuses on prompt gamma, shows that the depth profile of these emissions is highly correlated to the ions path and the measured counting rates allow to consider a realistic imaging system, operating in real time. For that purpose, we performed experiments at GANIL and at GSI with a collimated detector placed perpendicular to the beam axis and the time of flight technique was used in order to reduce the noise induced by neutrons and charged particles. Geant4 simulations were performed for the experimental design and data interpretation. A qualitative agreement between simulations and experiment is observed for the amount of energy deposited in the detector and the shape of the time of flight spectrum. However, discrepancies appear for the prompt gamma yield and the depth distribution of gamma detected. These discrepancies are discussed, mainly in terms of nuclear physics models that must be improved. After selecting the physical models which lead to the best agreement between simulations and measurements, studies on the location of prompt gamma emission and on the influence of diffusion in the target were performed to determine the impact on the correlation with the ion path

Hadron Therapy (HT) exploits properties of ion radiation to gain therapeutic advantages over existing photon-based forms of external radiation therapy. However, its relative superiority and cost-effectiveness have not been proven for all clinical situations. Establishing a robust evidence base for the development of best treatment practices is one of the major challenges for the field. This thesis investigates two research infrastructures for building this essential evidence. First, the thesis develops main components of a metadata-driven software architecture for the collection of clinical information and its analysis. This architecture acknowledges the diversity in the domain and supports data interoperability by sharing information models. Their compliance to common metamodels guarantees that primary data and analysis results can be interpreted outside of the immediate production context. This is a fundamental necessity for all aspects of the evidence creation process. A metamodel of data capture forms is developed with unique properties to support data collection and documentation in this architecture. The architecture's potential to support complex analysis processes is demonstrated with the help of a novel metamodel for Markov model based simulations, as used for the synthesis of evidence in health-economic assessments. The application of both metamodels is illustrated on the example of HT. Since the biological effect of particle radiation is a major source of uncertainty in HT, in its second part, this thesis undertakes first investigations towards a new research facility for bio-medical experiments with ion beams. It examines the feasibility of upgrading LEIR, an existing accelerator at the European Organisation for Nuclear Research (CERN), with a new slow extraction and investigates transport of the extracted beam to future experiments. Possible configurations for the slow-resonant extraction process are identified, and designs for horizontal and vertical beam transport lines developed. The results of these studies indicate future research directions towards a new ion beam facility for biomedical research.