Tesi sul tema "Proton therap"

Recent developments in high power, ultrashort pulse laser systems enable laser intensities beyond 10^21 W/cm^2 to be achieved. When focused onto thin foil targets, plasmas with extremely high electrostatic fields (>10^12V/m) are produced, resulting in the acceleration of protons/ions to very high energies (~60MeV). During my PhD, I have worked on experimental investigations into proton acceleration driven by high power laser pulses. Key to successful deployment of laser proton sources one one side is getting higher proton energies through to achieve the ultimate goal of realising table top machines for the treatment of cancer and on the other side, optimising the beam quality, an objective that was of the main motivation for my PhD work. My two main achievements were: 1. The production of bright, ultrashort and radially smooth pulsed proton beams using laser heating of pre-plasmas formed with long (nanosecond) pulses with ultrahigh intensity picosecond pulses. 2. Use of these beams to study the ultrafast dynamics of target implosion under intense laser irradiation The experiments on proton acceleration with the specific goal of controlling the proton beam quality by optical tool design, were performed at RAL. This scheme involves the use of multiple laser pulses to enhance and control the properties of beams of protons accelerated in ultra-intense laser irradiation of planar foil targets. Specifically, one laser pulse produces and controls the expansion of the target to enhance the energy coupling to the main (delayed) laser and/or drives shock deformation of the target to change the direction of the proton beam. The preplasma formed by this low intensity nanosecond beam (~ 0.5-5x10^12 W/cm^2) was used to enhance the laser absorption of the main (delayed) CPA (Chirped pulse amplified). The main CPA picosecond beam was used at high intensity (~ 4x 10^20 W /cm^2) to produce intense proton beams from the hydrogen rich target. The optimum intensity of the nanosecond beam was investigated and optimised to yield a very smooth and circular distribution of the proton beam achieved using a second long pulse laser at 5x10^12w/cm^2. The second achievement concerns an experiment also performed at RAL on proton radiography. As the laser based protons are characterised by small source size, high degree of collimation and short duration, they can be used in point projection backlighting schemes to perform radiography. In particular, I used this idea to perform radiography of a cylindrical target ~ 200µm long imploding under irradiation by long laser pulses of nanosecond duration. This allows measuring the degree of compression of the target as well as the stagnation time in the dynamic regime. The experiment took place in the framework of the HiPER project (the European High Power laser Energy Research facility Project). The final goal of the experiment was to study the transport of fast electron in cylindrical compressed target a subject of interest for fast ignition. In parallel to proton radiography x-ray radiography was used to compare the results. One of the specific advantages of using laser generated protons is that their spectrum is continuous upto a high energy cutoff. Because of their different time of flights protons proved to be very effective in revealing the implosion history of the target. In principle, the obtained implosion can be followed in time with a single shot sensitivity. Instead x-ray radiograph gives one image per laser shot at one fixed time and one has to make several shots in order to reveal the complete history of implosion. Another advantage of using proton radiography is a simpler experimental setup keeping imploding cylinder between proton target and proton detector on the same axis. Simulations of formation of proton images were made with the Monte Carlo MCNPX Code using the density profiles of the imploded cylinder obtained with the 2D-hydro CHIC code. A detailed study of Multiple Coulomb Scattering and Stopping Powers of the protons in low energy regimes for cold and warm matter was done to interpret the experimental results. Finally, I’m taking part in the analysis of experimental results obtained at the University of Rochester (USA) on the Omega-EP laser, and concerning magnetic field effect on the proton radiographs of a wired cone.

Cancer is ranked among the leading causes of death in the world. During the last decades, the development of advanced cancer treatment software has had an increasingly important role in its treatment. To treat cancer, there are many different therapies, one of which is radiation therapy. In radiation therapy, a central component of the treatment planning software is mathematical optimization of the radiation dose. This thesis concerns proton radiation therapy and aims to propose novel methods for generating advanced treatments using a new technique for delivering the radiation. In conventional proton therapy, the patient is irradiated from a few selected directions, typically two or three. To each irradiating direction corresponds a proton beam whose energy is modulated to control the depth at which the protons deposit their energy. This thesis concerns methods for an alternative technique, called proton arc therapy, where the central idea is to irradiate the patient from significantly more directions, but with fewer energies from each direction. This has the possibility of improving both the outcome and the efficiency of the treatment. The number of energies needs to be constrained due to the fact that they are the major determinant of the treatment delivery time, which is important as it is desired to irradiate the patient for as short time as possible. Thus, the central problem to be solved in proton arc therapy is which energies to use for irradiation at each possible angle. The work in this thesis aims at improving the state of the art by implementing methods for optimally solving this problem. When modeling the treatment as an optimization problem, the objective function is a quantitative evaluation criterion for the delivered dose distribution. In this work, the conventional optimization problem used for proton therapy is extended to proton arc therapy by including a constraint on the number of energies used over the arc. This problem is solved by using different algorithms and heuristics. The methods are evaluated on three different pancreatic tumor cases according to these evaluation criteria: objective function value, treatment delivery time and biological effect of the delivered dose. The developed methods are all able to produce proton arc treatments outperforming conventional treatments with respect to all the evaluation criteria. It is concluded that the proton arc therapy has the potential to outperform conventional proton therapy in all regards. The suggested method to perform the energy selection is a hybrid approach of greedy and reverse greedy algorithms. Future work should focus on the possibility of taking the biological effect into account in the optimization, as well as incorporating machine-specific constraints in the optimization model.
Cancer tillhör de främsta dödsorsakerna i världen. Under de senaste decennierna har utvecklingen av avancerad mjukvara haft en ökad betydelse för cancerbehandlingsplanering. Idag används flera metoder för att behandla cancer. Till dem hör strålterapi. Inom strålterapi är matematisk optimering av stråldosen en central komponent i den mjukvara som används för att ta fram behandlingsplaner. Detta examensarbete fokuserar på denna optimering specifikt inom protonterapi och syftar till att utveckla nya metoder för att generera avancerade behandlingar med en ny form av strålteknik. I konventionell protonterapi så strålas patienten från ett fåtal bestämda riktningar, vanligen två eller tre. Från varje riktning skjuts en protonstråle, vars energi moduleras för att kontrollera vid vilket djup protonerna levererar sin energi. Detta arbete behandlar en alternativ teknik som kallas protonbågsterapi, där den centrala idén är att stråla patienten från betydligt fler riktningar, men med färre energier från varje riktning. Denna teknik möjliggör förbättringar av behandlingens utfall liksom dess hastighet. Antalet protonenergier som används måste dock begränsas, eftersom ändringar av energin står för den primära tidsåtgången i behandlingen och det är önskvärt att stråla patienten under så kort tid som möjligt. Därmed är den centrala uppgiften i protonbågsterapi att bestämma vilka och hur många energier som ska användas från varje möjlig strålvinkel. Syftet med detta arbete är att ta fram metoder som presterar bättre än de befintliga för att lösa denna uppgift på ett optimalt sätt. När en strålbehandling modelleras som ett optimeringsproblem så är målfunktionen ett kvantitativt evalueringsmått baserat på den levererade dosfördelningen i patienten. I detta arbete utvidgas den konventionella problemformuleringen till att även involvera ett bivillkor avseende antalet energier som används i behandlingen. Problemet löses sedan med olika algoritmer och heuristiska metoder. Metoderna utvärderas genom att generera behandlingar i tre olika patientfall, samtliga med bukspottkörtelcancer. Tre krit erier utvärderas: målfunktionsvärde, behandlingstid samt dosens biologiska effekt. De utvecklade metoderna producerar samtliga behandlingar bättre än den som ges med konventionell protonterapi, med avseende på alla tre utvärderingskriterier. Således dras slutsatsen att protonbågsterapi kan vara en förbättring av konventionell protonterapi. Den föreslagna metoden för att välja energier är en hybridmetod bestående av en girig och en omvänt girig optimeringsmetod. Framtida arbete bör fokusera på att inkludera den biologiska effekten av dosen i optimeringsmodellen, och även att ta hänsyn till maskinspecifika begränsningar.

Aim: During proton therapy, neutrons are generated through the interactions of a proton beam with the treatment head and the patient’s body. A minor neutron dose to healthy tissues could be significant because of the high radiation weighting factor of neutrons. The aim of this research was to conduct a Monte Carlo (MC) simulation assessment of the relative neutron dose (neutron equivalent dose/prescribed proton therapy dose) and dose distribution during the proton irradiation at Clatterbridge Hospital. Materials and methods: Due to the required criteria for a neutron detector in a proton therapy room, a prototype neutron detector based on EJ-331 (gadolinium-loaded liquid scintillator) was simulated using Geant4 and GAMOS.4.0.0 MC simulation codes. Then, the detector was constructed, calibrated and tested. Four pulse shape discrimination (PSD) methods were obtained and evaluated: charges ratio, charge to amplitude ratio, amplitude-fall time and fall time-amplitude. The proton beam line at Clatterbridge Hospital was simulated using Geant4 and GAMOS.4.0.0 MC simulation codes. Neutrons and gamma rays were tracked during the proton irradiation and their deposited energies (DEs) were scored in a voxelised water phantom (50 x 100 x 50cm^3). The simulated prototype neutron detector was located 15cm in front of and 30cm below the final collimator of the simulated proton therapy beam line. In addition, measurement was taken using the prototype neutron detector during the proton irradiation at Clatterbridge Hospital. The measurement geometry was adjusted so that it was the same as the MC simulation geometry to allow a comparison with the MC simulation results and to validate the MC results. Results: The measured prototype neutron detector energy resolution was the same as the simulated detector, which was 17% at 477keV (Cs^137 Compton edge). Using a Figure of Merit to evaluate the obtained PSD methods, the best PSD method performance was found to be the charges ratio. Thus, the charges ratio PSD method was applied to the collected data from the measurements at the proton therapy room in Clatterbridge Hospital. A good agreement was found (within 80%) between the measured and the MC results. Hence, the MC simulation of the relative DE distributions from the neutrons and the gamma rays in the voxelised water phantom were validated. The MC simulation results showed that the contribution of gamma rays to the integral equivalent radiation dose was 5.1%. In addition, the contributions of internal and thermal neutrons to the integral equivalent neutron dose were 4.1% and 1.2% respectively. Thus, fast external neutrons are the main source (89.6%) of the secondary radiation dose during proton irradiation at Clatterbridge Hospital. Most of the neutron DE was distributed in and around the target voxel. In contrast, the gamma-ray DE was widely distributed. The relative integral neutron equivalent dose, which was 1.48mSv/Gy, and its distribution, in the patient’s body (i.e. the voxelised water phantom), can be generalised for any prescribed proton therapy dose during proton therapy at Clatterbridge Hospital. Conclusion: Fast external neutrons are the main concern in terms of the additional unwanted secondary radiation dose during proton therapy at the Clatterbridge proton beam. Although the neutron dose was small compared to the prescribed proton therapy dose, it is not negligible and the dose distribution can be used as the basis of the risk estimation from radiation induced secondary cancers.

Proton therapy is a relatively new treatment modality for cancer, having recently been incorporated into hospitals in the last two decades. Although proton therapy has much higher start up and treatment costs than traditional methods of radiotherapy, it continues to expand in use today. One reason for this is that proton therapy has the advantage of a more precise localization of dose compared to traditional radiotherapy. Other proposed advantages of proton therapy in the treatment of cancer may lead to a faster expanse in its use if proven to be more effective than traditional radiotherapy. Therefore, much research must be done to investigate the possible negative and positive effects of using proton therapy as a treatment modality. In proton therapy, protons do account for the vast majority of dose. However, when protons travel through matter, secondary particles are created by the interactions of protons and matter en route to and within the patient. It is believed that secondary dose can lead to secondary cancer, especially in pediatric cases. Therefore, the focus of this work is determining both primary and secondary dose. In order to develop relevant simulations, the specifications of the treatment room and beam were based off of real-world facilities as closely as possible. Using available data from proton accelerators and clinical facilities, an accurate proton therapy nozzle was designed. Dose calculations were performed by MCNPX using a simple water phantom, and then beam characteristics were investigated to ensure the accuracy of the model. After validation of the beam nozzle, primary and secondary dose values were tabulated and discussed. By demonstrating the method of these calculations, the purpose of this work is to serve as a guide into the relatively recent field of Monte Carlo methods in proton therapy.

En proton thérapie, la technique de balayage, permet de traiter efficacement le patient vis à vis de l'irradiation de la tumeur et la protection des tissus sains. Ces bénéfices dosimétriques peuvent cependant être grandement dégradés par les mouvements intra-fraction. Par conséquent, l'étude de méthodes d'atténuation ou d'adaptation est nécessaire. C'est pour cela, que nous avons développé un logiciel ”open-source” de calcul et d'évaluation de dose en 4D, MSPT (Motion Simulator for Proton Therapy), pour la technique de balayage. Son but est de mettre en avant l'impact des mouvements intra-fraction en calculant la répartition de dose dans le patient. En outre, l'utilisation de MSPT nous a permis de mettre au point et de proposer une nouvelle méthode d'atténuation du mouvement basée sur l'ajustement du poids du faisceau quand celui-ci balaye la tumeur. En photon thérapie, un enjeu principal pour les traitements délivrés à l'aide de collimateurs multi-lames (MLC) consiste à trouver un ensemble de configurations du MLC permettant d'irradier correctement la tumeur. L'efficacité d'un tel ensemble se mesure par le total beam-on time et le total setup time. Dans notre étude, nous nous intéressons à la minimisation de ces critères, d'un point de vue algorithmique, pour de nouvelles technologies de MLC: le MLC rotatif et le MLC à double couche. De plus, nous proposons un algorithme d'approximation pour trouver un ensemble de configurations minimisant le total beam-on time pour le MLC rotatif
In proton therapy, the delivery method named spot scanning, can provide a particularly efficient treatment in terms of tumor coverage and healthy tissues protection. The dosimetric benefits of proton therapy may be greatly degraded due to intra-fraction motions. Hence, the study of mitigation or adaptive methods is necessary. For this purpose, we developed an open-source 4D dose computation and evaluation software, MSPT (Motion Simulator for Proton Therapy), for the spot-scanning delivery technique. It aims at highlighting the impact of intra-fraction motions during a treatment delivery by computing the dose distribution in the moving patient. In addition, the use of MSPT allowed us to develop and propose a new motion mitigation strategy based on the adjustment of the beam's weight when the proton beam is scanning across the tumor. In photon therapy, a main concern for deliveries using a multileaf collimator (MLC) relies on finding a series of MLC configurations to deliver properly the treatment. The efficiency of such series is measured by the total beam-on time and the total setup time. In our work, we study the minimization of these efficiency criteria from an algorithmic point of view, for new variants of MLCs: the rotating MLC and the dual-layer MLC. In addition, we propose an approximation algorithm to find a series of configurations that minimizes the total beam-on time for the rotating MLC

The backprojection-then-filtering algorithm was applied to proton CT data to reconstruct a map of proton stopping power relative to water (RSP) in air, water and bone. Backprojections were performed along three commonly used path estimates for the proton: straight line path, cubic spline path, and most likely path. The proton CT data was obtained through simulations using the GEANT4 simulation toolkit. Two elliptical phantoms were inspected, and an accuracy of 0.2% and 0.8% was obtained for the RSP in water and bone respectively in the region of interest, while the RSP of air was significantly underestimated.

In a growing number of cutting edge centres around the world, radiotherapy treatments delivered by beams of protons and carbon ions offer the opportunity to target tumours with unprecedented conformality. But a sharper dose distribution increases the need for efficient quality control. Treatments are still affected by uncertainties on the penetration depth of the beam within the patient, requiring medical physicists to add safety margins. To reduce these margins and deliver safer treatments, different projects investigate real time range control by imaging prompt gammas emitted along the proton or carbon ion tracks in the patient.

This thesis reports on the feasibility, development and test of a new type of prompt gamma camera for proton therapy. This concept uses a knife-edge slit collimator to obtain a 1-dimensional projection of the beam path on a gamma camera. It was optimized, using the Monte Carlo code MCNPX version 2.5.0, to select high energy photons correlated with the beam range and detect them with both high counting statistics and sufficient spatial resolution for use in clinical routine. To validate the Monte Carlo model, spectrometry measurements of secondary particles emitted by a PMMA target during proton irradiation at 160 MeV were realised. An excellent agreement with the simulations was observed when using subtraction methods to isolate the gammas in direct incidence. A first prototype slit camera using the HiCam gamma detector was consequently prepared and tested successfully at 100 and 160 MeV beam energies. If we neglect electronic dead times and rejection of detected events, the current solution with its collimator at 15 cm from beam axis can achieve a 1-2 mm standard deviation on range estimation in a homogeneous PMMA target for numbers of protons that correspond to doses in water at Bragg peak as low as 15 cGy at 100 MeV and 25 cGy at 160 MeV assuming pencil beams with a Gaussian profile of 5 mm sigma at target entrance.

This thesis also investigates the applicability of the slit camera for carbon ion therapy. On the basis of Monte Carlo simulations with the code MCNPX version 2.7.E, this type of camera appears not to be able to identify the beam range with the required sensitivity. The feasibility of prompt gamma imaging itself seems questionable at high beam energies given the weak correlation of secondaries leaving the patient.

This work consequently concludes to the relevance of the slit camera approach for real time range monitoring in proton therapy, but not in carbon ion therapy.
Doctorat en Sciences de l'ingénieur
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Over the last few decades, radiotherapy using high-energy proton beams over the range from 50 MeV to 250 MeV has been increasingly used and developed. Indeed, it offers the possibility to focus the dose in a very narrow area around the tumor cells. The tumor control is improved compared to radiotherapy using photon beams and the healthy cells around the tumor are not irradiated since the range of charged particles is limited. However, due to nuclear reactions of the incident charged particles in the tissue, secondary high-energy radiations, essentially photons and neutrons, are produced and irradiate the treatment room.

As a consequence, thick concrete shielding walls are placed around the treatment room to ensure that other people and workers received a dose as small as possible. The dose measurement is performed with specific dosemeters such as the WENDI-II, which gives a conservative estimation of the ambient dose equivalent up to 5 GeV. The dose in working areas may also be estimated by means of numerical calculations by using simulation codes of particle transport such as the GEANT4, MCNPX, FLUKA and PHITS Monte Carlo codes.

Secondary particle yields calculated with Monte Carlo codes show discrepancies when different physical models are used but are globally in good agreement with experimental data from the literature. Neutron and photon doses decrease exponentially through concrete shielding wall but the neutron dose is definitely the main component behind a wall with sufficient thickness. Shielding parameters, e.g. attenuation coefficients, vary as functions of emission angle (regarding the incident beam direction), incident proton energy, and target material and composition.

The WENDI-II response functions computed by using different hadronic models show also some discrepancies. Thermal treatment of hydrogen in the polyethylene composing the detector is also of great importance to calculate the correct response function and the detector sensitivity.

Secondary particle sources in a proton therapy facility are essentially due to losses in cyclotron and beam interactions inside the energy selection system, with the treatment nozzle components and the target - patient or phantom. Numerical and experimental results of the dose in mazes show a good agreement for the most of detection points while they show large discrepancies in control rooms. Indeed, statistical consistency is reached with difficulty for both experimental and calculated results in control rooms since concrete walls are very thick in this case.

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La radiothérapie utilisant des faisceaux de protons d’énergie entre 50 MeV et 250 MeV s’est largement développée ces dernières années. Elle a l’immense avantage de pouvoir concentrer la dose due au faisceau incident de manière très efficace et très précise sur la tumeur, en épargnant les éventuels organes sains et sensibles aux radiations situés aux alentours. Cependant, des rayonnements « secondaires » très énergétiques sont créés par les réactions nucléaires subies par les protons lors de leur parcours dans les tissus, et peuvent sortir du patient. Des blindages entourant la salle de traitement et suffisamment épais doivent être présents afin que la dose reçue par les personnes se trouvant aux alentours soit la plus faible possible. La mesure de la dose se fait avec des dosimètres spécifiques et sensibles aux rayonnements de haute énergie, tels que le WENDI-II pour les neutrons. L’estimation de cette dose, et donc la modélisation des blindages, se fait également avec des codes de simulation numérique de transport de particules par les méthodes de Monte Carlo, tels que GEANT4, MCNPX, FLUKA et PHITS.

La production de rayonnements secondaires calculée à l’aide de codes Monte Carlo montre des écarts significatifs lorsque différents modèles d’interactions physiques sont utilisés, mais est en bon accord avec des données expérimentales de référence. L’atténuation de la dose due aux neutrons et aux photons secondaires à travers un blindage composé de béton est exponentielle. De plus, la dose due aux neutrons est clairement la composante dominante au-delà d’une certaine épaisseur. Les paramètres d’atténuation, comme par exemple le coefficient d’atténuation, dépendent de l’angle d’émission (par rapport à la direction du faisceau incident), de l’énergie des protons incidents et de la nature et la composition de la cible.

La fonction de réponse du dosimètre WENDI-II montre également des variations lorsque différents modèles physiques sont considérés dans les codes Monte Carlo. La prise en compte d’effets fins comme les états de vibration et de rotation des atomes d’hydrogène au sein du polyéthylène composant le détecteur se révèle essentielle afin de caractériser correctement la réponse du détecteur ainsi que sa sensibilité.

L’émission secondaire dans un centre de protonthérapie est essentiellement due aux pertes dans le cyclotron et aux interactions du faisceau avec les systèmes de sélection de l’énergie, les composants de la tête de tir et le patient (ou le fantôme). L’évaluation numérique de la dose dans les labyrinthes des différentes salles du centre montre un bon accord avec les données expérimentales. Tandis que pour les points de mesure dans leur salle de contrôle respective, de larges différences peuvent apparaitre. Ceci est en partie dû à la difficulté d’obtenir des résultats statistiquement recevables du point de vue expérimental, mais aussi numérique, au vu de l’épaisseur des blindages entourant les salles de contrôle.
Doctorat en Sciences de l'ingénieur
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This dissertation addresses the issue of robustness in proton therapy treatment planning for cancer treatment. Proton therapy is considered to be advantageous in treating most childhood cancers and certain adult cancers, including those of the skull base, spine and head and neck. Protons, unlike X-rays, have a finite range highly dependent on the electron density of the material they are traversing, resulting in a steep dose gradient at the distal edge of the Bragg peak. These characteristics, together with advancements in computation and technology have led to the ability to plan and deliver treatments with greater conformality, sparing normal tissue and organs at risk. Radiotherapy treatment plans aim to meet set dosimetric constraints, and meet them at every fraction. Plan robustness is a measure of deviation between the delivered dose distribution and the planned dose distribution. Due to the same characteristics that make protons advantageous, conventional means of using margins to create a Planning Target Volume (PTV) to ensure plan robustness are inadequate. Additional to this, without a PTV, a new method of analysing plan quality is required in proton therapy. My original contribution to the knowledge in this area is the demonstration of how site- and centre- specific robustness constraints can be established. Robustness constraints can be used both for proton plan analysis and to identify patients that require plans of greater individualisation. I have also used the daily volumetric imaging from patients previously treated with conventional radiotherapy to quantify range uncertainty from inter- and intra-fraction motion. These new methods of both quantifying and analysing the change in proton range in the patient can aid in the choice of beam directions, provide input into a multi- criteria optimisation algorithm or can be used as criteria to determine when adaptive planning may be required. This greater understanding in range uncertainty better informs the planner on how best to balance the trade-off between plan conformality and robustness in proton therapy. This research is directly relevant to furthering the knowledge base in light of HM Government pledging £250 million to build two proton centres in England, to treat NHS patients from 2018. Use of methods described in this dissertation will aid in the establishment of clear and pre-defined protocols for treating patients in the future.

Après une introduction à l’hadronthérapie et à la détection gamma prompts, cette thèse de doctorat comprend deux contributions principales: le développement d'une méthode de simulation des gamma prompt (PG) et son application dans une étude de la détection des changements dans les traitements cliniques. La méthode de réduction de variance (vpgTLE) est une méthode d'estimation de longueur de piste en deux étapes développée pour estimer le rendement en PG dans les volumes voxélisés. Comme les particules primaires se propagent tout au long de la CT du patient, les rendements de PG sont calculés en fonction de l'énergie actuelle du primaire, du matériau du voxel et de la longueur de l'étape. La deuxième étape utilise cette image intermédiaire comme source pour générer et propager le nombre de PG dans le reste de la géométrie de la scène, par exemple Dans un dispositif de détection. Pour un fantôme hétérogéné et un plan de traitement CT complet par rapport à MC analogue, à un niveau de convergence de 2% d'incertitude relative sur le rendement de PG par voxel dans la région de rendement de 90%, un gain d'environ 10^3 A été atteint. La méthode s'accorde avec les simulations analogiques MC de référence à moins de 10^-4 par voxel, avec un biais négligeable. La deuxième étude majeure menée dans portait sur l'estimation PG FOP dans les simulations cliniques. Le nombre de protons (poids spot) requis pour une estimation FOP constante a été étudié pour la première fois pour deux caméras PG optimisées, une fente multi-parallèle (MPS) et une conception de bordure de couteau (KES). Trois points ont été choisis pour une étude approfondie et, au niveau des points prescrits, on a constaté qu'ils produisaient des résultats insuffisants, ce qui rend improbable la production clinique utilisable sur le terrain. Lorsque le poids spot est artificiellement augmenté à 10^9 primaires, la précision sur le FOP atteint une précision millimétrique. Sur le décalage FOP, la caméra MPS fournit entre 0,71 - 1,02 mm (1sigma) de précision pour les trois points à 10 $ 9 $ de protons; Le KES entre 2.10 - 2.66 mm. Le regroupement de couches iso-énergétiques a été utilisé dans la détection par PG de distribution passive pour l'un des prototypes d'appareils PG. Dans le groupement iso-depth, activé par la livraison active, les taches avec des chutes de dose distales similaires sont regroupées de manière à fournir des retombées bien définies comme tentative de mélange de gamme de distance. Il est démontré que le regroupement de taches n'a pas nécessairement une incidence négative sur la précision par rapport à la tache artificiellement accrue, ce qui signifie qu'une certaine forme de groupage de points peut permettre l'utilisation clinique de ces caméras PG. Avec tous les spots ou les groupes spot, le MPS a un meilleur signal par rapport au KES, grâce à une plus grande efficacité de détection et à un niveau de fond inférieur en raison de la sélection du temps de vol
After an introduction to particle therapy and prompt gamma detection, this doctoral dissertation comprises two main contributions: the development of a fast prompt gammas (PGs) simulation method and its application in a study of change detectability in clinical treatments. The variance reduction method (named vpgTLE) is a two-stage track length estimation method developed to estimate the PG yield in voxelized volumes. As primary particles are propagated throughout the patient CT, the PG yields are computed as function of the current energy of the primary, the material in the voxel and the step length. The second stage uses this intermediate image as a source to generate and propagate the number of PGs throughout the rest of the scene geometry, e.g. into a detection device. For both a geometrical heterogeneous phantom and a complete patient CT treatment plan with respect to analog MC, at a convergence level of 2\% relative uncertainty on the PG yield per voxel in the 90\% yield region, a gain of around $10^3$ was achieved. The method agrees with reference analog MC simulations to within $10^{-4}$ per voxel, with negligible bias. The second major study conducted in this PhD program was on PG FOP estimation in clinical simulations. The number of protons (spot weight) required for a consistent FOP estimate was investigated for the first time for two optimized PG cameras, a multi-parallel slit (MPS) and a knife edge design (KES). Three spots were selected for an in depth study, and at the prescribed spot weights were found to produce results of insufficient precision, rendering usable clinical output on the spot level unlikely. When the spot weight is artificially increased to $10^9$ primaries, the precision on the FOP reaches millimetric precision. On the FOP shift the MPS camera provides between 0.71 - 1.02 mm (1$\upsigma$) precision for the three spots at $10^9$ protons; the KES between 2.10 - 2.66 mm. Grouping iso-energy layers was employed in passive delivery PG detection for one of the PG camera prototypes. In iso-depth grouping, enabled by active delivery, spots with similar distal dose fall-offs are grouped so as to provide well-defined fall-offs as an attempt to sidestep range mixing. It is shown that grouping spots does not necessarily negatively affect the precision compared to the artificially increased spot, which means some form of spot grouping can enable clinical use of these PG cameras. With all spots or spot groups the MPS has a better signal compared to the KES, thanks to a larger detection efficiency and a lower background level due to time of flight selection

La proton thérapie est une modalité de traitement du cancer qu’utilise des faisceaux de protons. Les systèmes de planification de traitement actuels se basent sur une image de l’anatomie du patient acquise par tomodensitométrie. Le pouvoir d’arrêt des protons relatif à l’eau (Stopping Power Ratio en Anglais, SPR) est déterminé à partir des unités Hounsfield (Hounsfield Units en Anglais, HU) pour calculer la dose absorbée au patient. Les protons sont plus vulnérables que les photons aux modifications du SPR du tissu dans la direction du faisceau dues au mouvement, désalignement ou changements anatomiques. De plus, les inexactitudes survenues de la CT de planification et intrinsèques à la conversion HU-SPR contribuent énormément à l’incertitude de la portée des protons. Dans la pratique clinique, au volume de traitement s’ajoutent des marges de sécurité pour tenir en compte ces incertitudes en détriment de perdre la capacité d’épargner les tissus autour de la tumeur. L’usage de l’imagerie bi-énergie en proton thérapie a été proposé pour la première fois en 2009 pour mieux estimer le SPR du patient par rapport à l’imagerie mono-énergie. Le but de cette thèse est d’étudier la potentielle amélioration de l’estimation du SPR des protons en utilisant l’imagerie bi-énergie, pour ainsi réduire l’incertitude dans la prédiction de la portée des protons dans le patient. Cette thèse est appliquée à un nouveau système d’imagerie, l’Imaging Ring (IR), un scanner de tomodensitométrie conique (Cone-Beam CT en Anglais, CBCT) développé pour la radiothérapie guidée par l’image. L’IR est équipé d’une source de rayons X avec un système d’alternance rapide du voltage, synchronisé avec une roue contenant des filtres de différents matériaux que permet des acquisitions CBCT multi-énergie. La première contribution est une méthode pour calibrer les modèles de source et la réponse du détecteur pour être utilisés en simulations d’imagerie X. Deuxièmement, les recherches ont évalué les facteurs que peuvent avoir un impact sur les résultats du procès de décomposition bi-énergie, dès paramètres d’acquisition au post-traitement. Les deux domaines, image et basée en la projection, ont été minutieusement étudiés, avec un spéciale accent aux approches basés en la projection. Deux nouvelles bases de décomposition ont été proposées pour estimer le SPR, sans avoir besoin d’une variable intermédiaire comme le nombre atomique effectif. La dernière partie propose une estimation du SPR des fantômes de caractérisation tissulaire et d’un fantôme anthropomorphique à partir d’acquisitions avec l’IR. Il a été implémentée une correction du diffusé, et il a été proposée une routine pour interpoler linéairement les sinogrammes de basse et haute énergie des acquisitions bi-énergie pour pouvoir réaliser des décompositions en matériaux avec données réelles. Les valeurs réconstruits du SPR ont été comparées aux valeurs du SPR expérimentales déterminés avec un faisceau d’ions de carbone
Proton therapy is a promising radiation treatment modality that uses proton beams to treat cancer. Current treatment planning systems rely on an X-ray computed tomography (CT) image of the patient's anatomy to design the treatment plan. The proton stopping-power ratio relative to water (SPR) is derived from CT numbers (HU) to compute the absorbed dose in the patient. Protons are more vulnerable than photons to changes in tissue SPR in the beam direction caused by movement, misalignment or anatomical changes. In addition, inaccuracies arising from the planning CT and intrinsic to the HU-SPR conversion greatly contribute to the proton range uncertainty. In clinical practice, safety margins are added to the treatment volume to account for these uncertainties at the expense of losing organ-sparing capabilities. The use of dual-energy (DE) in proton therapy was first suggested in 2009 to better estimate the SPR with respect to single-energy X-ray imaging. The aim of this thesis work is to investigate the potential improvement in determining proton SPR using DE to reduce the uncertainty in predicting the proton range in the patient. This PhD work is applied to a new imaging device, the Imaging Ring (IR), which is a cone-beam CT (CBCT) scanner developed for image-guided radiotherapy (IGRT). The IR is equipped with a fast kV switching X-ray source, synchronized with a filter wheel, allowing for multi-energy CBCT imaging. The first contribution of this thesis is a method to calibrate a model for the X-ray source and the detector response to be used in X-ray image simulations. It has been validated experimentally on three CBCT scanners. Secondly, the investigations have evaluated the factors that have an impact on the outcome of the DE decomposition process, from the acquisition parameters to the post-processing. Both image- and projection-based decomposition domains have been thoroughly investigated, with special emphasis on projection-based approaches. Two novel DE decomposition bases have been proposed to estimate proton SPRs, without the need for an intermediate variable such as the effective atomic number. The last part of the thesis proposes an estimation of proton SPR maps of tissue characterization and anthropomorphic phantoms through DE-CBCT acquisitions with the IR. A correction for X-ray scattering has been implemented off-line, and a routine to linearly interpolate low-energy and high-energy sinograms from sequential and fast-switching DE acquisitions has been proposed to perform DE material decomposition in the projection domain with real data. DECT-derived SPR values have been compared with experimentally-determined SPR values in a carbon-ion beam

Spatially fractionated radiation therapy (or grid) using megavoltage x-rays is a relatively new method of treating bulky (>8 cm) malignant tumors. Unlike the conventional approach in which the entire tumor is targeted with a nearly uniform radiation field, in grid the incident radiation is collimated with a special grid collimator. As such, only the volume under the open areas of the grid receives direct irradiation from the incident beam; the rest only sees scattered radiation and hence receives significantly less dose. Those regions seeing less dose serve as regrowth areas for normal tissues, thus reducing the normal tissue complication probability after the treatment. Although the grid dose distribution in a tumor is non-uniform, the regression of tumor mass has exhibited uniform regression clinically. Protons have two advantages over megavoltage x-rays which are typically used for grid: (1) protons scatter less in tissue, and (2) they have a fixed range in tissue (the Bragg peak) that can be used to target a tumor. The goal of this thesis is to computationally and experimentally assess the feasibility of grid using clinical proton beams. The proton pencil beams at the Provision Cancer Center in Knoxville, Tennessee, are used to create an array of beams mimicking the arrangement of beams in grid therapy. The dose distributions at various depths in a solid-water phantom are obtained computationally by the Monte Carlo code MCNP and validated by RayStation experimental Gafchromic film EBT3. The results are compared with those of the grid using megavoltage x-rays.

Bibliography: leaves 151-165.
A technique has been developed for measuring the energy spectra of high-energy proton therapy beams in situ under conditions similar to those used for radiotherapy at the South African National Accelerator Centre. The method is based on proton elastic scattering, H(p,p)H, in a thin polyethylene radiator and uses two ΔE-E detector telescopes to detect coincident proton pairs. Measurements have been made to investigate the effect of standard beam modification elements on the energy spectra of proton therapy beams produced by a passive scattering system. Monte Carlo simulations of the spectra were computed with the MCNPX 2.1.5 Monte Carlo code to compare with experimental measurements.

Magister Scientiae - MSc
Despite recent advances in radiotherapy, some tumours have shown to be resistant to treatment and patients still experience long term side effects. Gold nanoparticles (AuNPs) have been identified as effective radiosensitizers when employed concurrently with kilovoltage X-rays, which could selectively increase the dose delivered to a patient's tumour. The clinical application of proton radiation has gained renewed attention due to the lower integral body dose of protons compared to traditional X-ray based therapy. While extensive research has been formed on the behaviour of AuNPs in photon beams, limited information is available on the combination of AuNPs and proton radiation. Several questions remain regarding the interaction of protons with the AuNPs and possible dose enhancement effects at different depths along the Spread Out Bragg Peak (SOBP).

Proton therapy is one of the most advanced modalities for cancer treatments based on radiation, offering finite penetration depth, low energy deposition at the entrance and sharp dose fall-off. However some of its benefits may become a risk for the patient due to the uncertainties during treatment planning and dose delivery. This project investigates the feasibility of implementing a tool for the real time proton beam range verification in order to improve targeting accuracy and help to spare vital organs and healthy tissues as much as possible. The study is addressed to eye proton treatments. Here it is of key importance to obtain a good local control on the tumour while sparing the optical nerve and preserving the functionality of the eye. This involves surgically implanting a metal marker in the back of the eye between the tumour and the optic nerve and detecting the proton induced x-ray emissions (PIXE) generated by a therapeutic proton beam in the target. Preliminary experiments and Monte Carlo modelling were performed in an attempt to identify the parameters that will lead to the design of an ideal system. We focused on reducing the experimental background noise and op- timising the detection limit. PIXE signals were successfully acquired with a Cadmium Telluride (CdTe) detector at the Clatterbridge Cancer Centre (UK) and at the CATANA proton beam line (Italy). It was found that PIXE has a linear dependence with the proton fluence but it is energy dependent. This makes it unfeasible to be used for in vivo dosimetry. The most suitable metal was investigated and the minimum detectable residual range for gold and silver was assessed, even at clinical conditions. Statistical models for the multivariate analysis of the acquired data were implemented and a pos- sible use of PIXE was suggested in combination with the current treatment planning tools, to double check the correctness of a treatment delivery.

The aim of this study, carried out at the Center for Proton Therapy of the Paul Scherrer Institute (Villigen, Switzerland), involves the verification of the possibility of 4D treatments on patients requesting a patch field. This technique is used when the dimensions of the area to be irradiated are greater than 12 cm for the T direction and 20 cm for the U direction. We also went to research the setup that provides a better dose homogeneity, in order to mitigate the tumor's motion during the treatment. Three clinical cases were studied with the motions obtained from the respective 4DCT. Moreover, one of these was analyzed again simulating a motion extrapolated from a 4D-MRI. All 4 cases were analyzed in 9 combinations, 3 possible rescan scenarios (1, 4 and 8 rescan) and 3 different overlapping setups between the two patches (0, 1 and 2 cm of overlap). The values obtained were compared to the 3D plan. The dose homogeneity measures (D5-D95 and V95) showed that in the case of a slight motion (under 2 mm) there was no need to intervene with motion mitigation. For the motions classified of medium intensity (2-10 mm), it was found the need to introduce motion mitigation. In none of the previous cases, a systematic benefit emerged with a certain pattern of patch overlap. It was not possible to fully evaluate the last case, having a large motion (about 20 mm), as it needed an IMPT plan (technique not yet developed for the 4D), but still indications, regarding the benefit of the use of 8 rescan and greater possible overlap, emerged. The experimental measurements obtained at Gantry 2 with the use of a 2D detector (Octavius 1500 XDR), a gating system and a Quasar motion platform, confirmed that there are no problems with the actual dose release. The homogeneity of the dose is also found when there are extreme conditions, such as 2 cm overlap, 8 rescan and 4 patches (for a 4 cm zone receiving 32 rescan) and a strong simulated motion.

Purpose: To develop a Ray Cast/Dose Superposition (RC/DS) algorithm for proton grid therapy. Its functionality needed to include automatic positioning of small proton pencil beams in a grid-pattern and superimposing thin beam Monte Carlo (MC) dose distribution data on a Computer Tomography (CT) density volume. The purpose was to calculate and store un-weighted volumetric dose distributions of individual proton energies for subsequent optimization. Materials & Methods: Using the programming language Python 3.6, CT and Volume Of Interest (VOI) data of various patients and phantoms were imported. The target VOI was projected to either two or four planes, corresponding to the number of used gantry positions. Rays were then traced through the CT voxels, which were converted from Hounseld Units to density using a look up table, to calculate Water Equivalent Distance and proton energy needed to reach the proximal and distal edge of the target volume. With automated grid-pattern beam positioning, thin beam MC calculated depth dose distribution files were interpolated, scaled and superimposed on the CT volume for all beamlet positions. The algorithm reliability was tested on several CT image sets, the proton range estimation compared to a commercial TPS and the depth dose interpolation analyzed using MC simulations. Results: The RC/DS algorithm computation time was on average around 6 hours and 30 minutes for each CT set. The dose distribution output visually conformed to target locations and maintained a grid pattern for all tested CT sets. It gave unwanted dose artifacts in situations when rays outside the beamlet center passed a significant length of low/high density regions compared to the center, which yielded dose distributions of unlikely shape. Interpolating MC dose distribution values showed comparability to true MC references of same energy, yielding results with 0.5% difference in relative range and dose. Conclusions: The developed algorithm provides unweighted dose distributions specific for small beam proton grid therapy and has been shown to work for various setups and CT data. Un-optimized code caused longer computation times then intended but was presumed faster than MC simulations of the same setup. Efficiency and accuracy improvements are planed for in future work.
Proton grid therapy group

Malgré d’importants progrès, la tolérance des tissus sains aux rayonnements demeure un facteur central en radiothérapie, limitant par exemple l’efficacité du traitement des gliomes de haute grade. La proton thérapie avec mini-faisceaux (proton minibeam radiation therapy, pMBRT) est une nouvelle stratégie thérapeutique qui a pour objectif d’améliorer la préservation des tissus sains en combinant les avantages balistiques des protons et le fractionnement spatial de la dose obtenu avec des faisceaux submillimétriques. Dans ce contexte, la pMBRT a déjà démontré sa capacité à augmenter l’index thérapeutique dans le traitement des tumeurs cérébrales de rats. Un défi important est la génération des mini-faisceaux dans un cadre clinique : contrairement à la radiothérapie conventionnelle qui utilise des faisceaux larges (diamètre d’environ 5 mm à plusieurs centimètres), les mini-faisceaux se caractérisent par un diamètre de moins d’un millimètre. Actuellement, la génération des mini-faisceaux de protons est réalisée à l’aide de collimateurs mécaniques (blocs en métal avec plusieurs fentes ou trous) ce qui comporte plusieurs inconvénients (notamment une très faible flexibilité, une réduction importante du débit de dose ainsi que la génération de particules secondaires indésirables). Une solution optimale pourrait être la génération des mini-faisceaux par focalisation magnétique. Il en découle la question principale traitée dans cette thèse : Comment la génération des mini-faisceaux de protons par focalisation magnétique peut-elle être réalisée dans un cadre clinique ? En utilisant le modèle numérique d’un pencil beam scanning nozzle (le "nozzle" est la dernière partie d’une ligne de faisceau clinique), il a été démontré que les nozzles actuels ne sont pas adéquats pour focaliser les faisceaux de protons à la taille requise, les principales raisons étant une distance focale trop grande et une présence d’air excessive. En partant de ces conclusions, un nouveau design de nozzle optimisé a été développé. Ce nouveau modèle est capable de générer des mini-faisceaux de protons par focalisation magnétique dans des conditions réalisables avec les technologies existantes. Une étude Monte Carlo a également été menée afin de comparer et de quantifier les différences entre la génération de mini-faisceaux par collimation mécanique et par focalisation magnétique. Dans un second temps, cette thèse présente une évaluation des ions d’hélium comme alternative aux protons pour la radiothérapie avec mini-faisceaux. Il a pu être démontré que les ions d’hélium peuvent être un bon compromis en offrant certains des avantages dosimétriques observés avec les ions lourds sans les risques de toxicité associés
Despite major advances over the last decades, the dose tolerance of normal tissue continues to be a central problem in radiation therapy, limiting for example the effective treatment of hypoxic tumours and high-grade gliomas. Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy, combining the improved ballistics of protons with the enhanced tissue sparing potential of submillimetric, spatially fractionated beams (minibeams), that has already demonstrated its ability to significantly improve the therapeutic index for brain cancers in rats. In contrast to conventional proton therapy which uses comparatively large beam diameters of five millimetres to several centimetres, minibeams require beam sizes of less than 1 mm which are challenging to create in a clinical context. So far, every implementation of pMBRT at clinically relevant beam energies could only be achieved with the help of mechanical collimators (metal blocks with thin slits or holes). However, this method is inefficient, inflexible and creates high levels of unwanted secondary particles. The optimal approach may therefore be the generation of minibeams through magnetic focussing.This thesis investigates how magnetically focussed proton minibeams can be realised in a clinical context. Starting from the computer model of a modern pencil beam scanning nozzle (the term "nozzle" describes the final elements of a clinical beamline), it could be shown that current nozzles will not be suitable for this task, since their large dimensions and the presence of too much air in the beam path make it impossible to focus the beam down to the required sizes. Instead, an optimised nozzle design has been developed and evaluated with clinical beam models. It could be demonstrated that this design allows the generation of proton minibeams through magnetic focussing and that the new nozzle can be used with already existing technology. Moreover, a Monte Carlo study was performed to compare and quantify the differences between magnetically focussed minibeams and mechanically collimated minibeams.Finally, as the second aspect of this thesis, helium ions were evaluated as a potential alternative to protons for minibeam radiation therapy. It could be shown that helium ions could present a good compromise exhibiting many of the dosimetric advantages of heavier ions without the risks related to normal tissue toxicities

Accelerators play a key role in the delivery of radiotherapy for treatment of cancer and other medical conditions. Proton therapy has the benefit of more localised delivery of dose to deep seated tumour volumes in comparison to treatment using x-rays or electrons. The accelerators currently used for proton therapy are cyclotrons and synchrotrons, which each have certain advantages and disadvantages. It has been proposed that accelerators of a fixed field alternating gradient (FFAG) design may combine some of the advantages and avoid some of the disadvantages of the existing machines. This thesis looks at the use of synchrotrons as a benchmark for the delivery of proton therapy, and then at how FFAGs may improve upon treatment delivery. Particular attention is paid to the beam dynamics issues, including comparisons between simulations and experimental data taken with the EMMA non-scaling FFAG at Daresbury. The results of the comparisons show that simulation is able to predict the behaviour of a particle bunch in a real machine. The simulation tools are then used to evaluate the design of FFAGs incorporating resonant extraction techniques. In principle, resonant extraction could overcome some problems of kicker based extraction methods. The design study highlights technical challenges that would need to be overcome before resonant extraction could be implemented as a beneficial method for a proton therapy FFAG.

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.

Through this thesis we wanted to present a branch of radiotherapy that uses proton beams to destroy tumors, namely proton therapy. This technique, although relatively new (1946), is rapidly spreading thanks to the advantage of being able to precisely locate the release of the therapeutic dose of radiation. After a brief presentation of the discovery of ionizing radiations’ history and their possible applications, we focused on the study of the protons’ behavior when they interact with matter, going to show why they are so advantageous, by studying different quantities such as stopping power, flow rate, flow rate variation, multiple coulomb scattering and proton RBE. In fact, proton therapy represents a new and important therapeutic approach that allows a large part of healthy tissue to absorb less dose than in conventional therapies that use photons or electrons. The most interesting aspect of this thesis, and still with a broad future perspective, concerns the different types of detectors used in this therapy, which play a fundamental role in the progress of nuclear medicine, leading to ever better methods of prevention, diagnosis and treatment of illnesses. The future goal of this therapy is to develop new detectors, that are more equivalent to human tissues, both in behavior and detections, in order to obtain always better performances.

The physics of protons makes them well-suited to conformal radiotherapy due to the well-known Bragg peak effect. From a proton’s inherent stopping power, uncertainty effects can cause a small amount of dose to overflow to an organ at risk (OAR). Previous models for calculating normal tissue complication probabilities (NTCPs) relied on the equivalent uniform dose model (EUD), in which the organ was split into 1/3, 2/3 or whole organ irradiation. However, the problem of dealing with volumes < 1/3 of the total volume renders this EUD based approach no longer applicable. In this work the case for an experimental data-based replacement at low volumes is investigated. Lung fibrosis is investigated as an NTCP effect typically arising from dose overflow from tumour irradiation at the spinal base. Considering a 3D geometrical model of the lungs, irradiations are modelled with variable parameters of dose overflow. To calculate NTCPs without the EUD model, experimental data is used from the quantitative analysis of normal tissue effects in the clinic (QUANTEC) data. Additional side projects are also investigated, introduced and explained at various points. A typical radiotherapy course for the patient of 30×2Gy per fraction is simulated. A range of geometry of the target volume and irradiation types is investigated. Investigations with X-rays found the majority of the data point ratios (ratio of EUD values found from calculation based and data based methods) at ∼20% within unity showing a relatively close agreement. The ratios have not systematically preferred one particular type of predictive method. No Vx metric was found to consistently outperform another. In certain cases there is a good agreement and not in other cases which can be found predicted in the literature. The overall results leads to conclusion that there is no reason to discount the use of the data based predictive method particularly, as a low volume replacement predictive method.

Thesis (S.B. and S.M.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1998.
Includes bibliographical references (leaves 60-63).
A study was performed to develop a Monte Carlo method of modeling neutron shielding of proton therapy facilities in a complex, realistic environment. The bulk neutron shielding of the Northeast Proton Therapy Center (Massachusetts General Hospital, Boston, MA) was used as the basis of the design work. A geometrical model of the facility was simulated using the LAHET Code System, a set of Monte Carlo codes developed at Los Alamos National Laboratory. Additional software tools for reading and analyzing the simulation data that the model provides have been developed and tested. In order to verify the computer simulations, neutron detection and data acquisition systems have been assembled, modified, and thoroughly tested in order to monitor the neutron dose equivalent during proton beam operation at several locations on a continuous basis. Preliminary tests show that the geometry and physics models proposed in this work are valid.
by Michael R. Folkert.
S.B.and S.M.

The aim of this thesis is to investigate the use of a dedicated system for proton therapy treatments monitoring based on the PET technique. It focuses on the use of data acquired shortly after irradiations, which is currently not yet fully explored. An ad hoc detector called DoPET was built and used for several experiments. This stationary dual-head detector, along with an on-purpose optimised reconstruction software, is capable of reconstructing the β+ activated volume, acquiring data also during treatment for cyclotron based facilities. Currently, this system is one of the few PET systems worldwide for proton therapy monitoring that can be easily transported: it acquired data in three different particle therapy centres in Italy and in the proton therapy centre of Krakow, Poland. The FLUKA MC code was used for the validation and interpretation of our experimental data. FLUKA was chosen as a simulation tool because it has been intensively benchmarked against depth-dose data and lateral-dose profiles from various accelerators used for research and clinical ion-beam therapy. In this thesis, we present data acquired in two proton therapy centres with the aim of measuring the system monitoring capabilities in various conditions. The thesis is organized as follows: Chapter 1 provides a review of the physical rationale of particle therapy. In chapter 2, the DoPET system and its calibration process are described, along with the proton therapy centres where we have acquired data. Furthermore, we describe two methods of β+ activity reconstruction and the FLUKA MC code. Chapter 3 contains the experimental data analysis and their validation with FLUKA simulations, demonstrating that DoPET along with FLUKA can be used as a monitoring system for proton therapy. The last part of the chapter deals with the potential use of DoPET for beam characterisation. Finally, appendix A describes particle therapy technology and appendix B introduces a model for β + signal estimation.

The purpose of this thesis was to study the clinical implications of modern radiotherapy techniques for breast cancer treatment. This was investigated in several individual studies. Study I investigated the implications of using the analytical anisotropic algorithm (AAA) from the perspective of clinical recommendations for breast cancer radiotherapy. Pencil beam convolution plans of 40 breast cancer patients were recalculated with AAA. The latter plans had a significantly worse coverage of the planning target volume (PTV) with the 93% isodose, higher maximum dose in hotspots, higher volumes of the ipsilateral lung receiving doses below 25 Gy and smaller volumes with doses above 25 Gy. AAA also predicted lower doses to the heart. Study II investigated the implications of using the irregular surface compensator (ISC), an electronic compensation algorithm, in comparison to three‐dimensional conformal radiotherapy (3D‐CRT) for breast cancer treatment. Ten breast cancer patients were planned with both techniques. The ISC technique led to better coverage of the clinical target volume of the tumour bed (CTV‐T) and PTV in almost all patients with significant improvement in homogeneity. Study III investigated the feasibility of using scanning pencil beam proton therapy for regional and loco‐regional breast cancer with comparison of ISC photon planning. Ten patients were included in the study, all with dose heterogeneity in the target and/or hotspots in the normal tissues outside the PTV. The proton plans showed comparable or better CTV‐T and PTV coverage, with large reductions in the mean doses to the heart and the ipsilateral lung. Study IV investigated the added value of enhanced inspiration gating (EIG) for proton therapy. Twenty patients were planned on CT datasets acquired during EIG and freebreathing (FB) using photon 3D‐CRT and scanning proton therapy. Proton spot scanning has a high potential to reduce the irradiation of organs‐at‐risk for most patients, beyond what could be achieved with EIG and photon therapy, especially in terms of mean doses to the heart and the left anterior descending artery. Study V investigated the impact of physiological breathing motion during proton radiotherapy for breast cancer. Twelve thoracic patients were planned on CT datasets during breath‐hold at inhalation phase and breath‐hold at exhalation phase. Between inhalation and exhalation phase there were very small differences in dose delivered to the target and cardiovascular structures, with very small clinical implication. The results of these studies showed the potential of various radiotherapy techniques to improve the quality of life for breast cancer patients by limiting the dose burden for normal tissues.

This thesis focuses on advanced reconstruction methods and Dual Energy (DE) Computed Tomography (CT) applications for proton therapy, aiming at improving patient positioning and investigating approaches to deal with metal artifacts. To tackle the first goal, an algorithm for post-processing input DE images has been developed. The outputs are tumor- and bone-canceled images, which help in recognising structures in patient body. We proved that positioning error is substantially reduced using contrast enhanced images, thus suggesting the potential of such application. If positioning plays a key role in the delivery, even more important is the quality of planning CT. For that, modern CT scanners offer possibility to tackle challenging cases, like treatment of tumors close to metal implants. Possible approaches for dealing with artifacts introduced by such rods have been investigated experimentally at Paul Scherrer Institut (Switzerland), simulating several treatment plans on an anthropomorphic phantom. In particular, we examined the cases in which none, manual or Iterative Metal Artifact Reduction (iMAR) algorithm were used to correct the artifacts, using both Filtered Back Projection and Sinogram Affirmed Iterative Reconstruction as image reconstruction techniques. Moreover, direct stopping power calculation from DE images with iMAR has also been considered as alternative approach. Delivered dose measured with Gafchromic EBT3 films was compared with the one calculated in Treatment Planning System. Residual positioning errors, daily machine dependent uncertainties and film quenching have been taken into account in the analyses. Although plans with multiple fields seemed more robust than single field, results showed in general better agreement between prescribed and delivered dose when using iMAR, especially if combined with DE approach. Thus, we proved the potential of these advanced algorithms in improving dosimetry for plans in presence of metal implants.

Radiotherapy delivered using scanned beams of protons enables greater conformity between the dose distribution and the tumour than conventional radiotherapy using X rays. However, the dose distributions are more sensitive to changes in patient anatomy, and tend to deteriorate in the presence of motion. Online dose calculation during treatment delivery offers a way of monitoring the delivered dose in real time, and could be used as a basis for mitigating the effects of motion. The aim of this work has therefore been to investigate how the computational power offered by graphics processing units can be harnessed to enable fast analytical dose calculation for online monitoring in proton therapy. The first part of the work consisted of a systematic investigation of various approaches to implementing the most computationally expensive step of the pencil beam algorithm to run on graphics processing units. As a result, it was demonstrated how the kernel superposition operation, or convolution with a spatially varying kernel, can be efficiently implemented using a novel scatter-based approach. For the intended application, this outperformed the conventional gather-based approach suggested in the literature, permitting faster pencil beam dose calculation and potential speedups of related algorithms in other fields. In the second part, a parallelised proton therapy dose calculation engine employing the scatter-based kernel superposition implementation was developed. Such a dose calculation engine, running all of the principal steps of the pencil beam algorithm on a graphics processing unit, had not previously been presented in the literature. The accuracy of the calculation in the high- and medium-dose regions matched that of a clinical treatment planning system whilst the calculation was an order of magnitude faster than previously reported. Importantly, the calculation times were short, both compared to the dead time available during treatment delivery and to the typical motion period, making the implementation suitable for online calculation. In the final part, the beam model of the dose calculation engine was extended to account for the low-dose halo caused by particles travelling at large angles with the beam, making the algorithm comparable to those in current clinical use. By reusing the workflow of the initial calculation but employing a lower resolution for the halo calculation, it was demonstrated how the improved beam model could be included without prohibitively prolonging the calculation time. Since the implementation was based on a widely used algorithm, it was further predicted that by careful tuning, the dose calculation engine would be able to reproduce the dose from a general beamline with sufficient accuracy. Based on the presented results, it was concluded that, by using a single graphics processing unit, dose calculation using the pencil beam algorithm could be made sufficiently fast for online dose monitoring, whilst maintaining the accuracy of current clinical systems.

Proton radiation therapy allows for delivering a high dose to a well-confinedregion of interest due to the characteristic proton dose deposition. Due to protonrange straggling, anatomic variations in patients and small patient setup errors,treatment plans needs to account for proton range uncertainties of up to 3.5% invivo.Therefore, it is highly desirable to measure the proton range on-line in orderto minimize margins in the treatment plan. Initially, the feasibility of on-linerange monitoring through prompt gamma imaging and Positron EmissionTomography (PET) at different proton energies is evaluated using GEANT4Application for Tomographic Emission (GATE) Monte Carlo (MC) simulations.In the second phase, the performance of a lead knife-edge slit system for promptgamma imaging was evaluated with MC simulations. Results from simulationsindicate that prompt gamma emission and PET isotope production is correlatedwith proton range, with discrete prompt gamma emission lines from Carbon (4.4MeV) showing good correlation. The evaluated system was able to image thepeak gamma emission location at three different slit positions with promisingprecision ± 1 mm, ± 0.7 mm and ± 1.3 mm, and average shifts of -2 mm, -3 mmand -4 mm, respectively. The proton range was resolved with mean profile shiftsof -12 ± 1 mm, -13 ± 0.7 mm and -14 ± 1.3 mm, following prompt gamma crosssectionbehavior with peak emission- and threshold energies. The results providean indication of the potential of the knife-edge slit system and future work willinclude more extensive MC simulations and experimental measurements at the Skandion clinic to determine its clinical validity.
Strålbehandling av cancer med hjälp av protoner är fördelaktigt jämfört medkonventionell strålterapi då protonerna kan leverera en hög dos till ett välavgränsat område samtidigt som dosen till intilliggande vävnad effektivtreduceras. Tack vare statistiska variationer i protoners dosfördelning, anatomiskaavvikelser i patienter samt små fel vid patientfixering måste behandlingsplanerinnehålla marginaler som motsvarar ca 3.5% avvikelse i protonräckvidd. Att irealtid kunna mäta protoners räckvidd i patienten skulle vara tills stor nytta ochskulle bidra till att minska marginalerna i behandlingsplanen. I ett första skede avarbetet undersöktes möjligheten att avbilda protonräckvidden med promptgammaemission och Positron Emissions Tomografi (PET) genom GEANT4Application for Tomographic Emission (GATE) Monte Carlo (MC) simuleringar.Resultatet från MC simuleringarna användes sedan för att utvärdera ettdetektorsystem för prompt-gamma avbildning. Simuleringarna indikerade attproduktion av både prompt-gamma och PET isotoper är korrelerade medprotonernas räckvidd, särskilt 4.4 MeV emissionslinjen från Kol. Positionen förmaximal gamma emission kunde avbildas för tre olika positioner idetektorsystemet med en medelförskjutning på -2 ± 1 mm, -3 ± 0.7 mm och -4 ±1.3 mm. Detektorprofilen var förskjuten -12 ± 1 mm, -13 ± 0.7 mm och -14 ± 1.3mm jämfört med protonräckvidden p.g.a. interaktionernas energiberoende.Resultatet påvisar detektorsystemets potential att avbilda prompt-gamma fotoneroch framtida arbete omfattar ytterligare MC simuleringar och experimentellamätningar på Skandionklinken.

Proton radiotherapy is known to reduce the radiation dose delivered to normal healthy tissue compared to photon techniques. The increase in normal tissue sparing could result in fewer acute and late effects from radiation therapy. In this work proton therapy plans were created for patients previously treated using photon therapy. Intensity modulated proton therapy (IMPT) plans were planned using inverse planning in Varian's Eclipse treatment planning system with a scanning proton beam model to the same relative biological effectiveness (RBE)-weighted prescription dose as the photon plan. Proton and photon plans were compared for target dose conformity and homogeneity, body volumes receiving 2 Gy and 5 Gy, integral dose, dose to normal tissues and second cancer risk. Secondary cancer risk was determined using two methods. The relative risk of secondary cancer was found using the method described by Nguyen et al. by applying a linear relationship between integral dose and relative risk of secondary cancer. The second approach used Schneider et al.'s organ equivalent dose concept to describe the dose in the body and then calculate the excess absolute risk and cumulative risk for solid cancers in the body.IMPT and photon plans had similar target conformity and homogeneity. However IMPT plans had reduced integral dose and volumes of the body receiving low dose. Overall the risk of radiation induced secondary cancer was lower for IMPT plans compared to the corresponding photon plans with a reduction of ~36% using the integral dose model and ~50% using the organ equivalent dose model.
Un avantage connu de la radiothérapie par protons est la réduction de la dose reçue par les tissus normaux et sains par rapport aux traitements en photons. Cette réduction de dose peut résulter en une diminution des effets aigus et tardifs de la radiothérapie. Dans cet ouvrage, les plans de protonthérapie ont été créés pour des patients ayant été traités par radiothérapie en photons. Les plans de protonthérapie conformationnelle avec modulation d'intensité (PCMI) ont été conçus par planification inverse dans le système de planification de traitement Eclipse de Varian de façon à ce que le faisceau de protons en balayage produise la même dose de prescription que plan en photons, tout en tenant compte des efficacités biologiques relatives des deux types de radiation. Les plans en photons et en protons ont ensuite été comparés en termes de conformité de la dose, d'homogénéité de la dose, de volumes recevant 2 et 5 Gy, de dose intégrale, de dose aux tissus normaux et de risque de cancer secondaire. Le risque relatif de cancer secondaire a été determiné par la méthode décrite par Nguyen et al. en applicant une relation linéaire entre la dose intégrale et le risque relatif de cancer secondaire. Une deuxième approche employée dans cet ouvrage utilise le concept de dose équivalente à un organe de Schneider et al. pour décrire la dose dans le corps et par la suite calculer l'excès de risque absolu et le risque cumulatif de cancers solides dans le corps. Les traitements comparés, soit en photons et en protons, ont démontré une conformité et une homogénéité de la dose similaires dans le volume cible. Toutefois, les plans de PCMI réduisent la dose intégrale et diminuent les volumes du corps recevant une faible dose. Globalement, le risque d'induction d'un cancer secondaire est plus faible pour les plans de PCMI que pour les plans équivalents en photons avec une réduction de ~36% en utilisant le modèle de dose intégrale et ~50% en utilisant le modèle de dose équivalente à un organe.

Proton therapy is an established radiotherapy technique for the treatment of complex cancers. However, problems exist in the planning of treatments where the use of inaccurate dose modelling may lead to treatments being delivered which are not optimal. Most of the problems with dose modelling tools used in proton therapy treatment planning lie in their treatment of processes such as multiple Coulomb scattering, therefore a technique that accurately models such effects is preferable. Monte Carlo simulation alleviates many of the problems in current dose models but, at present, well-validated full-physics Monte Carlo simulations require more time than is practical in clinical use. Using the well-known and well-validated Monte Carlo toolkit Geant4, an application-called PTMC-has been developed for the simulation of proton therapy treatment plans. Using PTMC, several techniques to improve throughput were developed and evaluated, including changes to the tracking algorithm in Geant4 and application of large scale parallelism using novel computing architectures such as the Intel Xeon Phi co-processor. In order to quantify any differences in the dose-distributions simulated when applying these changes, a new dose comparison tool was also developed which is more suited than current techniques for use with Monte Carlo simulated dose distributions. Using an implementation of the Woodcock algorithm developed in this work, it is possible to track protons through a water phantom up to eight times faster than using the PRESTA algorithm present in Geant4, with negligible loss of accuracy. When applied to a patient simulation, the Woodcock algorithm increases throughput by up to thirty percent, though step limitation was necessary to preserve simulation accuracy. Parallelism was implemented on an Intel Xeon Phi co-processor card, where PTMC was tested with up to 244 concurrent threads. Difficulties imposed by the limited RAM available were overcome through the modification of the Geant4 toolkit and through the use of a novel dose collation technique. Using a single Xeon Phi co-processor, it is possible to validate a proton therapy treatment plan in two hours; with two co-processors that simulation time is halved. For the treatment plan tested, two Xeon Phi co-processors were roughly equivalent to a single 48-core AMD Opteron machine. The relative costs of Xeon Phi co-processors and traditional machines have also been investigated; at present the Intel Xeon Phi co-processor is not cost competitive with standard hardware, costing around twice as much as an AMD machine with comparable performance. Distributed parallelism was also implemented through the use of the Google Compute Engine (GCE). A tool has been developed-called PYPE-which allows users to launch large clusters in the GCE to perform arbitrary compute-intensive work. PYPE was used with PTMC to perform rapid treatment plan validation in the GCE. Using a large cluster, it is possible to validate a proton therapy treatment plan in ten minutes at a cost of roughly $10; the same plan computed locally on a 24-thread Intel Xeon machine required five hours. As an example calculation using PYPE and PTMC, a robustness study is undertaken for a proton therapy treatment plan; this robustness study shows the usefulness of Monte Carlo when computing dose distributions for robustness studies, and the utility of the PYPE tool to make numerous full physics Monte Carlo simulations quickly. Using the tools developed in this work, a complete treatment plan robustness study can be performed in around 26 hours for a cost of less than $500, while using full-physics Monte Carlo for dose distribution calculations.

In this thesis, a study of neutron production properties for collimator materials is performed. Collimators are used in nuclear physics applications such as within the fields of nuclear energy and radiotherapy. The area of application is primarily reduction of static or unwanted radiation for detectors and treatment beams. This study focuses on a branch of radiotherapy called proton therapy where protons of high energies impinge on the collimator. Proton therapy has advantages compared to common radiotherapy techniques due to the energy deposition characteristics of protons. However, high-energy protons cause nuclear reactions in the dose delivery equipment, especially in the collimators. These reactions produce neutron radiation which is both hazardous and difficult to shield from. The choice of different collimator materials has previously not been thoroughly evaluated with respect to neutron production. In this thesis, the neutron production properties of different materials have been evaluated by running simulations with the Monte Carlo particle transport code MCNPX. In an initial survey, some materials of particular interest could be identified. In a second stage, dose calculations in a patient dummy, i.e., a water phantom, were performed. This was done in order to confirm that the lower neutron production of the interesting materials could reduce the biological effect. It is shown that common collimator materials presently used indeed are suboptimal with respect to neutron production. The common collimator material tungsten should not be recommended for use based on the result of this study. Replacing it with nickel, iron or brass will reduce the neutron dose by approximately 30%, which would lead to a reduction of late effects due to proton treatments.

Background: In treatment planning for intensity-modulated proton therapy (IMPT), we aim to deliver the prescribed dose to the target yet minimize the dose to adjacent healthy tissue. Mixed-integer programming (MIP) has been applied in radiation therapy to generate treatment plans. However, MIP has not been used effectively for IMPT treatment planning with dose-volume constraints. In this study, we incorporated dose-volume constraints in an MIP model to generate treatment plans for IMPT. Methods: We created a new MIP model for IMPT with dose volume constraints. Two groups of IMPT treatment plans were generated for each of three patients by using MIP models for a total of six plans: one plan was derived with the Limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) method while the other plan was derived with our MIP model with dose-volume constraints. We then compared these two plans by dose-volume histogram (DVH) indices to evaluate the performance of the new MIP model with dose-volume constraints. In addition, we developed a model to more efficiently find the best balance between tumor coverage and normal tissue protection. Results: The MIP model with dose-volume constraints generates IMPT treatment plans with comparable target dose coverage, target dose homogeneity, and the maximum dose to organs at risk (OARs) compared to treatment plans from the conventional quadratic programming method without any tedious trial-and-error process. Some notable reduction in the mean doses of OARs is observed. Conclusions: The treatment plans from our MIP model with dose-volume constraints can meetall dose-volume constraints for OARs and targets without any tedious trial-and-error process. This model has the potential to automatically generate IMPT plans with consistent plan quality among different treatment planners and across institutions and better protection for important parallel OARs in an effective way.

This thesis describes the design of novel magnetic lattices for the transport line and gantry of a charged particle therapy complex. The designs use non-scaling Fixed Field Alternating Gradient (ns-FFAG) magnets and were made as part of the PAMELA project. The main contributions in this thesis are the near-perfect FFAG dispersion suppression design process and the designs of the transport line and the gantry lattices. The primary challenge when designing an FFAG gantry is that particles with different momenta take up different lateral positions within the magnets. This is called dispersion and causes problems at three points: the entrance to the gantry, which must be rotated without distortion of the beam; at the end of the gantry where reduced dispersion is required for entry to the scanning system; and a third of the way through the gantry, where a switch in curvature of the magnets is required. Due to their non-linear fields, dispersion suppression in conventional FFAGs is never perfect. However, as this thesis shows, a solution can be found through manipulation of the field components, meaning near-perfect dispersion suppression can be achieved using ns-FFAG magnets (although at a cost of irregular optics). The design process for an FFAG dispersion suppressor shown in this thesis is a novel solution to a previously unsolved problem. Other challenges in the gantry lattice design, such as height and the control of the optics, are tackled and a final gantry design presented and discussed. The starting point for the transport line is a straight FFAG lattice design. This is optimised and matched to a 45o bend. Fixed field solutions to the problem of extracting to the treatment room are discussed, but a time variable field solution is decided on for practical and patient safety reasons. A matching scheme into the gantry room is then designed and presented.

La thérapie proton est utilisée dans le cadre du traitement contre le cancer afin de parvenir à une meilleure distribution de dose en exploitant les propriétés du proton. Les systèmes de planification de thérapie proton requièrent une carte du pouvoir d’arrêt des tissus du patient afin de pouvoir calculer la dose absorbée. En clinique, cette image est générée à partir d’une conversion des unités Hounsfield d’une image tomodensitométrique (CT) rayons X au pouvoir d’arrêt relatif (RSP) du proton. Cette calibration induit des incertitudes étant donné que les interactions physiques des photons et des protons sont différentes, ce qui va mener à l’utilisation de marges de sécurité et à la réduction de la conformité de dose. Afin de réduire ces incertitudes, l’imagerie proton CT a été proposée pour la planification de la thérapie proton puisque la quantité reconstruite est directement le RSP. En plus de la perte d’énergie, les protons interagissent également via la diffusion multiple de Coulomb (MCS) qui induit des trajectoires non linéaires, ce qui rend le problème de reconstruction en proton CT différent de la reconstruction CT rayons X. L’objectif de cette thèse est l’amélioration de la qualité d’image en reconstruction proton CT en mode liste. L’utilisation du formalisme du chemin le plus probable (MLP) afin de prendre en compte les effets du MCS a permis d’améliorer la résolution spatiale en proton CT. Ce formalisme suppose un milieu homogène. La première contribution de cette thèse est une étude sur les trajectoires des protons en milieux hétérogènes: la justesse du MLP a été évaluée en comparaison avec un MLP obtenu par simulations Monte Carlo dans différentes configurations. Les résultats en matière de distribution spatiale, angulaire, et énergétique ont été analysés afin d’évaluer l’impact sur l’image reconstruite. La seconde contribution est un filtre rampe directionnel 2D utilisé dans le cadre de la reconstruction proton CT. Il s’agit d’une méthode intermédiaire entre la rétroprojection filtrée et le filtrage de la rétroprojection, basée sur l’extension du filtre rampe en 2D afin de préserver l’information spatiale sur le MLP. Une expression pour une version 2D limitée en bande de fréquence du filtre rampe a été dérivée et testée sur des données pCT simulées. Ensuite, une comparaison de différents algorithmes de reconstruction directs en matière de résolution spatiale et justesse du RSP a été menée. Cinq algorithmes, incluant le filtre rampe directionnel, ont été testés afin de reconstruire différents fantômes. Les résultats obtenus à partir de données acquises avec des détecteurs idéaux ou réalistes ont été comparés. Enfin, la dernière contribution est une méthode de déconvolution qui utilise l’information sur l’incertitude du MLP afin d’améliorer la résolution des images proton CT
Proton therapy is used for cancer treatment to achieve better dose conformity by exploiting the energy-loss properties of protons. Proton treatment planning systems require knowledge of the stopping-power map of the patient’s anatomy to compute the absorbed dose. In clinical practice, this map is generated through a conversion from X-ray computed tomography (CT) Hounsfield units to proton stopping power relative to water (RSP). This calibration generates uncertainties as photon and proton physics are different, which leads to the use of safety margins and the reduction of dose conformity. In order to reduce uncertainties, proton CT (pCT) was proposed as a planning imaging modality since the reconstructed quantity is directly the RSP. In addition to energy loss, protons also undergo multiple Coulomb scattering (MCS) inducing non-linear paths, thus making the pCT reconstruction problem different from that of X-ray CT. The objective of this thesis is to improve image quality of pCT list-mode reconstruction. The use of a most likely path (MLP) formalism for protons to account for the effects of MCS has improved the spatial resolution in pCT. This formalism assumes a homogeneous medium. The first contribution of this thesis is a study on proton paths in heteregeneous media: the accuracy of the MLP was evaluated against a Monte Carlo generated path in different heterogeneous configurations. Results in terms of spatial, angular, and energy distributions were analyzed to assess the impact on reconstruction. The second contribution is a 2D directional ramp filter used for pCT data reconstruction. An intermediate between a filtered backprojection and a backproject-filter approach was proposed, based on the extension of the usual ramp filter to two dimensions, in order to preserve the MLP spatial information. An expression for a band-limited 2D version of the ramp filter was derived and tested on simulated pCT list-mode data. Then, a comparison of direct reconstruction algorithms in terms of spatial resolution and RSP accuracy was conducted. Five algorithms, including the 2D directional ramp, were tested to reconstruct different simulated phantoms. Results were compared between reconstruction from data acquired using idealized or realistic trackers. Finally, the last contribution is a deconvolution method using the information on the MLP uncertainty in order to improve spatial resolution of pCT images

Thesis advisor: Michael Graf
The purpose of this dissertation was to investigate the temporal limit on the ability to measure temperature changes using magnetic resonance imaging (MRI). The limit was examined in experiments using a variety of imaging techniques for MRI-based temperature measurements. We applied these methods for monitoring temperature changes in focused ultrasound (FUS) heating experiments. FUS is an attractive alternative to surgical resection due to its noninvasive character. FUS treatments have been successfully conducted in several clinical applications. MRI and MR thermometry is a natural choice for the guidance of FUS surgeries, given its ability to visualize, monitor, and evaluate the success of treatments. MR thermometry, however, can be a very challenging application, as good resolution is often needed along spatial, temporal as well as temperature axes. These three quantities are strictly related to each other, and normally it is theoretically impossible to simultaneously achieve high resolutions for all axes. In this dissertation, techniques were developed to achieve this at cost of some reduction in spatial coverage. Given that the heated foci produced during thermal therapies are typically much smaller than the anatomy being imaged, much of the imaged field-of-view is not actually being heated and may not require temperature monitoring. By sacrificing some of the in-plane spatial coverage outside the region-of-interest (ROI), significant gains can be obtained in terms of temporal resolution. In the extreme, an ROI can be chosen to be a narrow pencil-like column, and a sampling time for temperature imaging is possible with a temporal resolution of a few milliseconds. MRI-based thermal imaging, which maps temperature-induced changes in the proton resonance frequency, was implemented in two projects. In the first project, three previously described, fast MR imaging techniques were combined in a hybrid method to significantly speed up acquisition compared to the conventional thermometry. Acceleration factors up to 24-fold were obtained, and a temporal resolution as high as 320 milliseconds was achieved. The method was tested in a gel phantom and in bovine muscle samples in FUS heating experiments. The robustness of the hybrid method with respect to the cancellation of the fat signal, which causes temperature errors, and the incorporation of the method into an ultrafast, three dimensional sequence were also investigated. In the second project, a novel MR spectroscopic sequence was investigated for ultrafast one-dimension thermometry. Temperature monitoring was examined during FUS sonications in a gel phantom, SNR performance was evaluated in vivo in a rabbit brain, and feasibility was tested in a human heart. It was shown capable in a FUS heating experiment in a gel phantom of increasing temporal resolution to as high as 53 milliseconds in a three Tesla MRI. The temporal resolution achieved is an order of magnitude faster than any other rapid MR thermometry sequences reported. With this one-dimensional approach, a short sampling time as low as 3.6 milliseconds was theoretically achievable. However, given the SNR that could be achieved and the limited heating induced by FUS in the gel phantom in a few milliseconds, any temperature changes in such a short period were obscured by noise. We have analyzed the conditions whereby a temporal resolution of a few-milliseconds could be obtained
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Physics

Background The finite range of a proton beam in tissue and the corresponding steep distal dose gradient near the end of the particle track open new vistas for the delivery of a highly target-conformal dose distribution in radiation therapy. Compared to a classical photon treatment, the potential therapeutic benefit of a particle treatment is a significant dose reduction in the tumor-surrounding tissue at a comparable dose level applied to the tumor. Motivation The actually applied particle range, and therefor the dose deposition in the target volume, is quite sensitive to the tissue composition in the path of the protons. Particle treatments are planned via computed tomography images, acquired prior to the treatment. The conversion from photon stopping power to proton stopping power induces an important source of range-uncertainty. Furthermore, anatomical deviations from planning situation affect the accurate dose deposition. Since there is no clinical routine measurement of the actually applied particle range, treatments are currently planned to be robust in favor of optimal regarding the dose delivery. Robust planning incorporates the application of safety margins around the tumor volume as well as the usage of (potentially) unfavorable field directions. These pretreatment safety procedures aim to secure dose conformality in the tumor volume, however at the price of additional dose to the surrounding tissue. As a result, the unverified particle range constraints the principle benefit of proton therapy. An on-line, in-vivo range-verification would therefore bring the potential of particle therapy much closer to the daily clinical routine. Materials and methods This work contributes to the field of in-vivo treatment verification by the methodical investigation of range assessment via the detection of prompt gamma-rays, a side product emitted due to proton-tissue interaction. In the first part, the concept of measuring the spatial prompt gamma-ray emission profile with a Compton camera is investigated with a prototype system consisting of a CdZnTe cross strip detector as scatter plane and three side-by-side arranged, segmented BGO block detectors as absorber planes. In the second part, the novel method of prompt gamma-ray timing (PGT) is introduced. This technique has been developed in the scope of this work and a patent has been applied for. The necessary physical considerations for PGT are outlined and the feasibility of the method is supported with first proof-of-principle experiments. Results Compton camera: Utilizing a 22-Na source, the feasibility of reconstructing the emission scene of a point source at 1.275 MeV was verified. Suitable filters on the scatter-absorber coincident timing and the respective sum energy were defined and applied to the data. The source position and corresponding source displacements could be verified in the reconstructed Compton images. In a next step, a Compton imaging test at 4.44 MeV photon energy was performed. A suitable test setup was identified at the Tandetron accelerator at the Helmholtz-Zentrum Dresden-Rossendorf, Germany. This measurement setup provided a monoenergetic, point-like source of 4.44 MeV gamma-rays, that was nearly free of background. Here, the absolute gamma-ray yield was determined. The Compton imaging prototype was tested at the Tandetron regarding (i) the energy resolution, timing resolution, and spatial resolution of the individual detectors, (ii) the imaging capabilities of the prototype at 4.44 MeV gamma-ray energy and (iii) the Compton imaging efficiency. In a Compton imaging test, the source position and the corresponding source displacements were verified in the reconstructed Compton images. Furthermore, via the quantitative gamma-ray emission yield, the Compton imaging efficiency at 4.44 MeV photon energy was determined experimentally. PGT: The concept of PGT was developed and introduced to the scientific community in the scope of this thesis. A theoretical model for PGT was developed and outlined. Based on the theoretical considerations, a Monte Carlo (MC) algorithm, capable of simulating PGT distributions was implemented. At the KVI-CART proton beam line in Groningen, The Netherlands, time-resolved prompt gamma-ray spectra were recorded with a small scale, scintillator based detection system. The recorded data were analyzed in the scope of PGT and compared to the measured data, yielding in an excellent agreement and thus verifying the developed theoretical basis. For a hypothetical PGT imaging setup at a therapeutic proton beam it was shown, that the statistical error on the range determination could be reduced to 5 mm at a 90 % confidence level for a single spot of 5x10E8 protons. Conclusion Compton imaging and PGT were investigated as candidates for treatment verification, based on the detection of prompt gamma-rays. The feasibility of Compton imaging at photon energies of several MeV was proven, which supports the approach of imaging high energetic prompt $gamma$-rays. However, the applicability of a Compton camera under therapeutic conditions was found to be questionable, due to (i) the low device detection efficiency and the corresponding limited number of valid events, that can be recorded within a single treatment and utilized for image reconstruction, and (ii) the complexity of the detector setup and attached readout electronics, which make the development of a clinical prototype expensive and time consuming. PGT is based on a simple time-spectroscopic measurement approach. The collimation-less detection principle implies a high detection efficiency compared to the Compton camera. The promising results on the applicability under treatment conditions and the simplicity of the detector setup qualify PGT as method well suited for a fast translation towards a clinical trial
Hintergrund Strahlentherapie ist eine wichtige Modalität der therapeutischen Behandlung von Krebs. Das Ziel dieser Behandlungsform ist die Applikation einer bestimmten Strahlendosis im Tumorvolumen, wobei umliegendes, gesundes Gewebe nach Möglichkeit geschont werden soll. Bei der Bestrahlung mit einem hochenergetischen Protonenstrahl erlaubt die wohldefinierte Reichweite der Teilchen im Gewebe, in Kombination mit dem steilen, distalen Dosisgradienten, eine hohe Tumor-Konformalität der deponierten Dosis. Verglichen mit der klassisch eingesetzten Behandlung mit Photonen ergibt sich für eine optimiert geplante Behandlung mit Protonen ein deutlich reduziertes Dosisnivau im den Tumor umgebenden Gewebe. Motivation Die tatsächlich applizierte Reichweite der Protonen im Körper, und somit auch die lokal deponierte Dosis, ist stark abhängig vom Bremsvermögen der Materie im Strahlengang der Protonen. Bestrahlungspläne werden mit Hilfe eines Computertomographen (CT) erstellt, wobei die CT Bilder vor der eigentlichen Behandlung aufgenommen werden. Ein CT misst allerdings lediglich den linearen Schwächungskoeffizienten für Photonen in der Einheit Hounsfield Units (HU). Die Ungenauigkeit in der Umrechnung von HU in Protonen-Bremsvermögen ist, unter anderem, eine wesentliche Ursache für die Unsicherheit über die tatsächliche Reichweite der Protonen im Körper des Patienten. Derzeit existiert keine routinemäßige Methode, um die applizierte Dosis oder auch die Protonenreichweite in-vivo und in Echtzeit zu bestimmen. Um das geplante Dosisniveau im Tumorvolumen trotz möglicher Reichweiteunterschiede zu gewährleisten, werden die Bestrahlungspläne für Protonen auf Robustheit optimiert, was zum Einen das geplante Dosisniveau im Tumorvolumen trotz auftretender Reichweiteveränderungen sicherstellen soll, zum Anderen aber auf Kosten der möglichen Dosiseinsparung im gesunden Gewebe geht. Zusammengefasst kann der Hauptvorteil einer Therapie mit Protonen wegen der Unsicherheit über die tatsächlich applizierte Reichweite nicht wirklich realisiert. Eine Methode zur Bestimmung der Reichweite in-vivo und in Echtzeit wäre daher von großem Nutzen, um das theoretische Potential der Protonentherapie auch in der praktisch ausschöpfen zu können. Material und Methoden In dieser Arbeit werden zwei Konzepte zur Messung prompter Gamma-Strahlung behandelt, welche potentiell zur Bestimmung der Reichweite der Protonen im Körper eingesetzt werden können. Prompte Gamma-Strahlung entsteht durch Proton-Atomkern-Kollision auf einer Zeitskala unterhalb von Picosekunden entlang des Strahlweges der Protonen im Gewebe. Aufgrund der prompten Emission ist diese Form der Sekundärstrahlung ein aussichtsreicher Kandidat für eine Bestrahlungs-Verifikation in Echtzeit. Zum Einen wird die Anwendbarkeit von Compton-Kameras anhand eines Prototyps untersucht. Dabei zielt die Messung auf die Rekonstruktion des örtlichen Emissionsprofils der prompten Gammas ab. Zum Zweiten wird eine, im Rahmen dieser Arbeit neu entwickelte Messmethode, das Prompt Gamma-Ray Timing (PGT), vorgestellt und international zum Patent angemeldet. Im Gegensatz zu bereits bekannten Ansätzen, verwendet PGT die endliche Flugzeit der Protonen durch das Gewebe und bestimmt zeitliche Emissionsprofile der prompten Gammas. Ergebnisse Compton Kamera: Die örtliche Emissionsverteilung einer punktförmigen 22-Na Quelle wurde wurde bei einer Photonenenergie von 1.275 MeV nachgewiesen. Dabei konnten sowohl die absolute Quellposition als auch laterale Verschiebungen der Quelle rekonstruiert werden. Da prompte Gamma-Strahlung Emissionsenergien von einigen MeV aufweist, wurde als nächster Schritt ein Bildrekonstruktionstest bei 4.44 MeV durchgeführt. Ein geeignetes Testsetup wurde am Tandetron Beschleuniger am Helmholtz-Zentrum Dresden-Rossendorf, Deutschland, identifiziert, wo eine monoenergetische, punktförmige Emissionverteilung von 4.44 MeV Photonen erzeugt werden konnte. Für die Detektoren des Prototyps wurden zum Einen die örtliche und zeitliche Auflösung sowie die Energieauflösungen untersucht. Zum Anderen wurde die Emissionsverteilung der erzeugten 4.44 MeV Quelle rekonstruiert und die zugehörige Effizienz des Prototyps experimentell bestimmt. PGT: Für das neu vorgeschlagene Messverfahren PGT wurden im Rahmen dieser Arbeit die theoretischen Grundlagen ausgearbeitet und dargestellt. Darauf basierend, wurde ein Monte Carlo (MC) Code entwickelt, welcher die Modellierung von PGT Spektren ermöglicht. Am Protonenstrahl des Kernfysisch Verschneller Institut (KVI), Groningen, Niederlande, wurden zeitaufgelöste Spektren prompter Gammastrahlung aufgenommen und analysiert. Durch einen Vergleich von experimentellen und modellierten Daten konnte die Gültigkeit der vorgelegten theoretischen Überlegungen quantitativ bestätigt werden. Anhand eines hypothetischen Bestrahlungsszenarios wurde gezeigt, dass der statistische Fehler in der Bestimmung der Reichweite mit einer Genauigkeit von 5 mm bei einem Konfidenzniveau von 90 % für einen einzelnen starken Spot 5x10E8 Protonen mit PGT erreichbar ist. Schlussfolgerungen Für den Compton Kamera Prototyp wurde gezeigt, dass eine Bildgebung für Gamma-Energien einiger MeV, wie sie bei prompter Gammastrahlung auftreten, möglich ist. Allerdings erlaubt die prinzipielle Abbildbarkeit noch keine Nutzbarkeit unter therapeutischen Strahlbedingungen nicht. Der wesentliche und in dieser Arbeit nachgewiesene Hinderungsgrund liegt in der niedrigen (gemessenen) Nachweiseffizienz, welche die Anzahl der validen Daten, die für die Bildrekonstruktion genutzt werden können, drastisch einschränkt. PGT basiert, im Gegensatz zur Compton Kamera, auf einem einfachen zeit-spektroskopischen Messaufbau. Die kollimatorfreie Messmethode erlaubt eine gute Nachweiseffizienz und kann somit den statistischen Fehler bei der Reichweitenbestimmung auf ein klinisch relevantes Niveau reduzieren. Die guten Ergebnissen und die ausgeführten Abschätzungen für therapeutische Bedingungen lassen erwarten, dass PGT als Grundlage für eine Bestrahlungsverifiktation in-vivo und in Echtzeit zügig klinisch umgesetzt werden kann

Thesis (S.M. and S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2009.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 69-70).
PURPOSE: Prompt gamma rays emitted from proton-nucleus interactions in tissue present a promising non-invasive, in situ means of monitoring proton beam based radiotherapy. This study investigates the fluence and energy distribution of prompt gamma rays emitted during proton irradiation of phantoms. This information was used to develop a correlation between the measured and calculated gamma emission and the proton beam range, which would allow treatments to more effectively exploit the sharp distal falloff in the dose distributions of protons. METHOD & MATERIALS: A model of a cylindrical Lucite phantom with a monoenergetic proton beam and an annular array of ideal photon tallies arranged orthogonal to the beam was developed using the Monte Carlo code MCNPX 2.6.0. Heterogeneous geometries were studied by inserting metal implants into the Lucite phantom, and simulating a phantom composed of bone and lung equivalent materials and polymethyl methacrylate. RESULTS: Experimental and computational results indicated a correlation between gamma emission and the proton depth-dose profile. Several peaks were evident in the calculated energy spectrum and the 4.44 MeV emission from 12C was the most intense line having any apparent correlation with the depth dose profile. Arbitrary energy binning of 4-5 MeV and 4-8 MeV was performed on the Monte Carlo data; this binned data yielded a distinct emission peak 1cm proximal to the Bragg peak. In all cases in the Lucite phantom the position of the Bragg peak's 80% distal falloff corresponded with the position of the 4-8MeV binned 50% distal falloff. The 4-5MeV binning strategy was successful with the heterogeneous phantom in which the proton beam entered lung and stopped in bone. However, the density disparity between the bone and lung equivalent materials rendered this technique unsuccessful for the heterogeneous phantom in which the beam entered bone and stopped in lung. For this 1.4MeV binning was conducted, assessing the 1.37 MeV characteristic gamma peak of 24Mg, which was only present in the lung slab. CONCLUSIONS: The results are promising and indicate the feasibility of prompt gamma emission detection as a means of characterizing the proton beam range in situ. This study has established the measurement and omputational tools necessary to pursue the development of this technique.
by John R. Styczynski.
S.M.and S.B.

Summary in English.
Bibliography: pages 125-129.
This thesis describes the construction and use of the facemask at the National Accelerator Centre (NAC) as used to both immobilise and position patients for precision proton radiotherapy. The precision achieved using the stereophotogrammetric (SPG) positioning system is measured, and the shortcomings and errors in using the facemask by the SPG system are measured and analysed. The implementation of improvements made to the SPG system is reported upon, and alternative means of both supporting the fiducial markers and immobilising the patient are investigated and evaluated. The accuracy of positioning a facemask using the SPG system is 1.4 mm and of positioning a newly designed frame is 1.6 mm. These measurements were made without using a patient. It is estimated that the total uncertainty of positioning a patient's tumour at the isocentre is 1.6 (1SD) mm using the facemask and it is estimated that the precision using the frame will be less than this value. The largest component of this error (1.39 mm) is due to the error in obtaining the CT scanner co-ordinates. These results are comparable to those obtained by other investigators. The movement of patient bony landmarks within the facemask was measured to be 1.0 ± 0.8 mm. Three main recommendations are that the CT scanner co-ordinating procedure be improved, the SPG computer program be rewritten in parts to achieve greater speed and accuracy, and that the new frame be used. The frame is easier to manufacture than the facemask and allows real time monitoring of the position of the patient's head by the SPG system thus allowing faster throughput of patients and better positioning quality control.

During proton therapy both target volumes and healthy tissue, including organs at risk (OARs), receives radiation dose. Thus, radiotherapy is a trade-off between good target coverage and OAR sparing. For protons, most of the dose is deposited right before it is stopped, a phenomenon termed the Bragg peak. Beyond this point no dose will be deposited, which is an advantageous feature since it enables more OAR sparing. However, this feature also makes proton therapy sensitive to variations in patient position, uncertainties in dose calculation and geometry/anatomy changes. Geometrical margins are therefore added around the target volume to ensure proper coverage.  An evaluation of the margins and plan robustness for proton therapy of unilateral tonsil cancer was conducted in this study, where the endpoint was to further optimize the margins to account for the trade-off between target coverage and doses to OAR. Verification CTs were compared with the plan CT of seven patients using the software Elastix and MICE toolkit. Dose volume histograms (DVHs) were evaluated together with Hausdorff distances (HdD), target coverage and dose differences along the craniocaudal direction, and related to the patient vertebrae.  Tendencies for the need of larger margins caudally of the cervical vertebra C3 was concluded from the HdD and two patients were selected for replanning. Four new treatment plans were created for each patient in the treatment planning system Eclipse and the resulting proton dose distributions were evaluated in MICE toolkit. Two plans utilized a uniform uncertainty of 4 and 5 mm respectively, and two plans utilized a varying uncertainty around the CTV.  Since Eclipse only allows the user to evaluate and optimize a plan with uniform setup uncertainty, new structures for the CTV had to be created for the varying uncertainty before the optimization. Caudally of C3 added PTV margins of 2 and 3 mm were created. Thereafter these new structures were evaluated and optimized with a setup uncertainty of 3 mm.  The limited available data suggests that the treatment plans with varying margins shows favorable characteristics and may improve the treatment quality. Tendencies for improved balance between target coverage and OAR sparing could be seen for the plan with a PTV margin of 3 mm caudally of C3 and a setup uncertainty of 3 mm. However, more patients need to be included in the study before certain conclusions can be made.

Ce manuscrit de thèse présente la synthèse de nanoparticules d’oxyde de fer superparamagnétiques couramment appelées SPIONs servant d’agents de contraste pour l’imagerie par résonance magnétique (IRM) et la génération de chaleur pour la thérapie cellulaire par hyperthermie induite par champ magnétique radiofréquence (HMRF). Le contrôle des tailles et de la distribution en tailles des SPIONs et donc de leurs propriétés magnétiques a été obtenu en utilisant un copolymère arborescent G1 (substrat de polystyrène branché en peigne noté G0, greffé avec des groupements pendants poly(2-vinyle pyridine) ) comme milieu « gabarit », tandis que la stabilité colloïdale et la biocompatibilité des SPIONs ont été apportées par un procédé de poly-complexation ionique grâce à un copolymère double-hydrophile acide polyacrylique-bloc-poly(acrylate de 2-hydroxyéthyle) PAA-b-PHEA
This Ph.D. dissertation describes the synthesis of superparamagnetic iron oxide nanoparticles (SPIONs) designed to serve as magnetic resonance imaging (MRI) contrast agents and for heat generation in cellular radiofrequency magnetic field hyperthermia (MFH) treatment. Control over the size and size distribution of the iron oxide nanoparticles (NPs), and thus over their magnetic properties, was achieved using a G1 arborescent copolymer (comb-branched (G0) polystyrene substrate grafted with poly(2-vinylpyridine) side chains, or G0PS-g-P2VP) as a template. Good colloidal stability and biocompatibility of the SPIONs were achieved via the formation of polyion complex (PIC) micelles with a poly(acrylic acid)-block-poly(2-hydroxyethyl acrylate) (PAA-b-PHEA) double-hydrophilic block copolymer