<p>Predmet istraživanja ove doktorske disertacije<br />je osiguranje kvaliteta u radioterapiji. U okviru<br />rada na disertaciji je sprovedena klinička<br />verifikacija sistema za planiranje terapije u<br />vedim radioterapijskim centrima u Srbiji sa<br />ciljem obezbeđivanja optimalnog kori&scaron;denja<br />TPS i bezbedne radioterapije. Ova verifikacija<br />predstavlja bitan deo QA radioterapijskog<br />procesa, gde se nakon početne verifikacije<br />prikupljeni podaci koriste i za dalje periodične<br />provere u okviru osiguranja kvaliteta. Dalje<br />istraživanje je sprovedeno u cilju<br />implementacije in vivo dozimetrije u kliničku<br />praksu kao veoma bitne procedure za<br />osiguranje kvaliteta čitavog radioterapijskog<br />procesa, od preskripcije do isporuke doze. Na<br />taj način su određeni nivoi tolerancije/akcije za<br />različite grupe pacijenata i određene<br />radioterapijske tehnike. Takođe, procenjena je<br />tačnost radioterapijskog procesa na Institutu za<br />onkologiju Vojvodine u Sremskoj Kamenici.</p> / <p>The subject of this dissertation is quality<br />assurance (QA) in radiotherapy. As part of the<br />thesis was conducted clinical verification of<br />treatment planning systems (TPS) in major<br />radiotherapy centers in Serbia in order to<br />ensure the optimal usage of TPS and safe<br />radiotherapy. This TPS verification is an<br />important part of radiotherapy QA process,<br />where after an initial verification of the data<br />collected and then used for further periodic<br />checks as part of quality assurance. Further<br />research was conducted in order to implement<br />in vivo dosimetry in clinical practice as a very<br />important procedure for quality assurance of<br />the entire radiotherapy process, from<br />prescription to dose delivery. In this way,<br />tolerance/actions levels for different groups of<br />patients and specific radiation technique were<br />determined. Also, the accuracy of the<br />radiotherapy process at the Institute of<br />oncology of Vojvodina in Sremska Kamenica<br />was estimated.</p>

A Radioterapia de lesões cerebrais próximas a estruturas críticas necessitam de uma alta precisão na localização e na dose. O rigor na liberação da dose deve ser acompanhado por um preciso controle da qualidade nos aparelhos que envolvam a prática. O comissionamento do sistema de planejamento consiste em averiguar e confirmar os cálculos realizados pelo sistema. Porém, mesmo com todo controle da qualidade no comissionamento, existem vários aspectos que podem influenciar na administração da dose no volume alvo, o que exige a necessidade de se fazer uma avaliação final, no ato do tratamento, in vivo. O objetivo deste trabalho é desenvolver uma técnica de dosimetria in vivo como parte de um programa de controle da qualidade em radioterapia estereotáxica. Na técnica de dosimetria in vivo, utilizaram-se segmentos de filme radiocrômico, com dimensões de 1x1 cm2, acoplados na área externa ao colimador formado por micro-lâminas, Moduleaf. Estes filmes foram inseridos na região central do feixe. Os filmes foram irradiados e calibrados para obtenção dos fatores campos, na configuração da técnica. Com estes dados foi elaborado um programa computacional, o qual calcula a densidade relativa que um filme deve adquirir quando submetido a uma exposição nesta configuração. Como a técnica de dosimetria in vivo usa os dados do TPS, validaram-se alguns parâmetros do comissionamento do TPS. Complementando o estudo da dosimetria in vivo foram avaliados cinco planos não co-planares, sendo o primeiro com 15 campos e os outros com 25 campos. Antes de iniciar o procedimento o segmento de filme era acoplado ao aparelho e após a execução do tratamento a densidade ótica era avaliada e comparada com a calculada pelo programa desenvolvido. No comissionamento, todas as dosimetrias relativas apresentaram diferenças percentuais menores que 2%, quando comparados os resultados medidos com os calculados pelo sistema de planejamento. No desenvolvimento da técnica de dosimetria in vivo, a diferença percentual média da verificação dosimétrica, no momento da irradiação, comparado com a calculada pela planilha foi de 1,5%, enquanto que a dosimetria absoluta aplicada ao controle da qualidade convencional foi aprovada com diferença percentual média de 2,5% e a função gama média encontrada foi de 97,9% dos pontos aprovados com critério de aceitação %=2% e D=2 mm. Logo, todos os dados estão em concordância com os limites estabelecidos pelo TRS-430. Desta forma, conclui-se que foi desenvolvida uma técnica de dosimetria in vivo como parte de um programa de controle da qualidade em radioterapia estereotáxica com filme radiocrômico, já que foram confirmados os parâmetros básicos do comissionamento do sistema de planejamento e a técnica foi validada com o controle de qualidade convencional nos cinco planos analisados. / Radiation therapy of brain lesions near critical structures requires a highly accurate location and dose. The accuracy in dose delivery should be accompanied by an accurate quality control in devices involving the practice. The commissioning of the planning system is to ascertain and confirm the calculations performed by the system, but even with all quality control in the commissioning, there are several aspects that may influence the dosing the target volume, which necessitates the need to make a final assessment at the time of treatment, in vivo. The objective of this work is to develop a technique for in vivo dosimetry as part of quality assurance in stereotactic radiotherapy. In vivo dosimetry technique, we used segments of film radiocrômico, with dimensions of 1x1 cm2, coupled to the external area formed by the micro-collimator blades, Moduleaf. These films were inserted in the central region of the beam. The films were irradiated and calibrated to obtain factors of fields in the configuration of the technique. With these data we designed a computer program which calculates the relative density of a film must acquire when subjected to an exposure in this setting. As the technique of in vivo dosimetry using data from the TPS, validated parameters are the commissioning of the TPS. Complementing the study of in vivo dosimetry were evaluated five non-coplanar plans, the first with 15 fields and the other with 25 fields. Before starting the procedure, the film segment was attached to the unit and after the treatment is the optical density was measured and compared with those calculated by the program developed. At commissioning, all presented on dosimetry percentage differences less than 2%, when comparing the measured results with those calculated by the planning system. In developing the technique of in vivo dosimetry, the mean percent difference dosimetry verification at the time of irradiation compared with the calculated by the sheet was 1.5%, while the absolute dosimetry applied to the conventional quality control has been approved as mean percent difference 2.5% and the gamma function mean was 97.9% of the points agreed with the acceptance criterion % = 2% and D = 2 mm. Therefore, all data are in agreement with the limits set by TRS-430. Thus, we conclude that we have developed a technique for in vivo dosimetry as part of a quality assurance in stereotactic radiotherapy radiocrômico film, since some parameters were confirmed to commissioning the planning system and the technique was validated with control quality standard in five plans analyzed.

Apesar da introdução do controle da qualidade individual nas técnicas complexas de tratamentos, tem-se comprovado que, mesmo assim, é possível a ocorrência de erros na aplicação da dose no momento da aplicação. No entanto, ainda não estão bem estabelecidas as ferramentas de redundância a fim de controlar a dose no momento da terapêutica, além do que, as técnicas mais modernas de tratamento radioterápico desenvolvem as aplicações com feixes rotacionais e os dosímetros tradicionalmente utilizados em controle da qualidade oferecem limitações angulares. Assim, este trabalho vem contribuir para o desenvolvimento de uma metodologia de controle da qualidade de transmissão in vivo utilizando filmes radiocrômicos acoplados ao cabeçote do acelerador linear, durante aplicações radioterápicas nas técnicas de tratamento conformacional e IMRT. A metodologia de controle da qualidade desenvolvida neste trabalho baseia-se na obtenção da distribuição de dose in vivo de tratamentos radioterápicos com um filme radiocrômico EBT2 posicionado em um suporte acrílico, semelhante a uma bandeja, a uma distância fonte-superfície de 56,8 cm, acoplado ao acessório holder do acelerador linear durante a aplicação de todo o tratamento teleterápico. Posteriormente, foi realizada uma análise gama para comparação da distribuição de dose medida pelo filme com a esperada pelo sistema de planejamento, obtida no plano coronal e central de um objeto simulador, com dimensões semelhantes ao suporte acrílico, posicionado à distância de 100 cm, como resultado da transferência do plano em questão. Com os resultados encontrados na seção conformacional, avaliando tanto a simulação Monte Carlo quanto as irradiações, pode-se concluir que a diferença entre a distribuição de dose do sistema de planejamento, na distância foco detector de 100 cm, e do filme, na distância de 56,8 cm, é diminuta e, desta forma, é viável criar uma metodologia para verificação dosimétrica de transmissão utilizando o filme radiocrômico acoplado ao cabeçote do acelerador. O controle da qualidade proposto na técnica de IMRT concordou com o esperado em 24 das 25 situações testadas, apresentando apenas um resultado diferente, ou seja, uma concordância de 96% com o esperado. As avaliações in vivo concordaram com 98% dos controles avaliados. Desta forma, pode-se concluir que a metodologia proposta neste trabalho é factível para o controle da qualidade de transmissão in vivo, em tratamentos radioterápicos que usam a técnica de tratamento conformacional e IMRT e, como ela não oferece dificuldades para o deslocamento angular do gantry, ela poderá ser aplicada em técnicas teleterápicas mais modernas. / Even with the introduction of the individual quality control in the complex techniques of radiation therapy treatments, the occurrence of errors in the release of the dose at the time of application is possible. However, in order to monitor the dose at the time of therapy, redundancy tools are not yet well established, Besides that, the most modern techniques of radiation treatment use rotational beams to deliver the desired dose distributions and the dosimeters traditionally used in quality control of radiation therapy suffer angular limitations. In this way, this work aims to contribute to the development of a methodology of transmission quality control in vivo presenting a dose control technique using radiochromic film coupled to the headstock linear accelerator for radiotherapy applications to monitor conformational techniques and IMRT treatment. The quality control methodology developed in this work is based on obtaining the in vivo dose distribution of radiotherapy treatments with a radiochromic film EBT2, positioned on an acrylic stand, similar to a tray at a source-surface distance of 56.8 cm, coupled to the linear accelerator accessory holder during application of any treatment. It was subsequently performed a gama analysis for comparison of the dose distribution measured by the film with the expected dose distribution by the treatment planning system. The expected dose distribution was obtained in the coronal and central plane of a phantom, with similar dimensions to the acrylic stand and positioned on a source-surface distance of 100 cm as a result of the transfer of the plan in question. Based on the results presented in the conformational section, evaluating both, Monte Carlo simulation and irradiation results, it can be concluded that the difference between the distribution of the dose planning system, focus distance 100 cm detector, and the film, on distance of 56.8 cm, are small, and in this way it is feasible to create a methodology for dosimetry verification using radiochromic film coupled to the head of the accelerator. The proposed quality control in IMRT technique agreed with expected in 24 simulations of the 25 situations tested, showing only one different result, i.e., there was a 96% concordance with the expected. In this way, it can be concluded that the methodology proposed in this work is feasible for the in vivo quality control of radiation therapy treatments that use the conformational and IMRT treatment techniques, and also can be applied to the most modern radiotherapy techniques since, it does not offer difficulties with the angular displacement of the gantry.

La radiothérapie moderne combine les techniques complexes et les traitements personnalisés, avec le risque que certaines évolutions et erreurs ayant lieu au cours de traitement passent inaperçues. Ces aléas peuvent entraîner des conséquences graves pour la santé du patient. Dans cette perspective, nous avons étudié le potentiel d'un système de dosimétrie in vivo de transit pour le suivi continu du patient et, par conséquent, la radiothérapie adaptative. L'expérience clinique et des tests de faisabilité ont permis de définir les axes de travail principaux: l'automatisation et la simplification du procédé d'analyse des contrôles. Les développements incluent la création d'une bibliothèque de données standard et une série d'analyses de causes racines, permettant ainsi de renforcer la précision du système, d'améliorer l'automatisation de sa mise en place et d'identifier des pistes pour une analyse efficace des résultats et pour la création d'outils supplémentaires facilitant le suivi et l'adaptation du traitement en routine clinique. / Modern radiation therapy combines complex techniques and personalized treatments, with the risk that certain evolutions and errors occurring during the course of the treatment might go unnoticed. These fluctuations may cause great damage to the health of the patient. In this perspective, we worked on the potential of a transit in vivo dosimetry system for continuous monitoring of the patient and, hereafter, adaptive radiotherapy. Our clinical experience and feasibility testing determined the main lines of work : automatization and simplification of the results analysis method. The developments included the creation of a golden data library and a series of root cause analyzes, allowing us to strengthen the accuracy of the system, to enhance the automatization of the setup and to identify tracks for an efficient analysis of the results and for the creation of additional analytical tools to facilitate the monitoring and adaptation of the treatments in clinical routine.

Apesar da introdução do controle da qualidade individual nas técnicas complexas de tratamentos, tem-se comprovado que, mesmo assim, é possível a ocorrência de erros na aplicação da dose no momento da aplicação. No entanto, ainda não estão bem estabelecidas as ferramentas de redundância a fim de controlar a dose no momento da terapêutica, além do que, as técnicas mais modernas de tratamento radioterápico desenvolvem as aplicações com feixes rotacionais e os dosímetros tradicionalmente utilizados em controle da qualidade oferecem limitações angulares. Assim, este trabalho vem contribuir para o desenvolvimento de uma metodologia de controle da qualidade de transmissão in vivo utilizando filmes radiocrômicos acoplados ao cabeçote do acelerador linear, durante aplicações radioterápicas nas técnicas de tratamento conformacional e IMRT. A metodologia de controle da qualidade desenvolvida neste trabalho baseia-se na obtenção da distribuição de dose in vivo de tratamentos radioterápicos com um filme radiocrômico EBT2 posicionado em um suporte acrílico, semelhante a uma bandeja, a uma distância fonte-superfície de 56,8 cm, acoplado ao acessório holder do acelerador linear durante a aplicação de todo o tratamento teleterápico. Posteriormente, foi realizada uma análise gama para comparação da distribuição de dose medida pelo filme com a esperada pelo sistema de planejamento, obtida no plano coronal e central de um objeto simulador, com dimensões semelhantes ao suporte acrílico, posicionado à distância de 100 cm, como resultado da transferência do plano em questão. Com os resultados encontrados na seção conformacional, avaliando tanto a simulação Monte Carlo quanto as irradiações, pode-se concluir que a diferença entre a distribuição de dose do sistema de planejamento, na distância foco detector de 100 cm, e do filme, na distância de 56,8 cm, é diminuta e, desta forma, é viável criar uma metodologia para verificação dosimétrica de transmissão utilizando o filme radiocrômico acoplado ao cabeçote do acelerador. O controle da qualidade proposto na técnica de IMRT concordou com o esperado em 24 das 25 situações testadas, apresentando apenas um resultado diferente, ou seja, uma concordância de 96% com o esperado. As avaliações in vivo concordaram com 98% dos controles avaliados. Desta forma, pode-se concluir que a metodologia proposta neste trabalho é factível para o controle da qualidade de transmissão in vivo, em tratamentos radioterápicos que usam a técnica de tratamento conformacional e IMRT e, como ela não oferece dificuldades para o deslocamento angular do gantry, ela poderá ser aplicada em técnicas teleterápicas mais modernas. / Even with the introduction of the individual quality control in the complex techniques of radiation therapy treatments, the occurrence of errors in the release of the dose at the time of application is possible. However, in order to monitor the dose at the time of therapy, redundancy tools are not yet well established, Besides that, the most modern techniques of radiation treatment use rotational beams to deliver the desired dose distributions and the dosimeters traditionally used in quality control of radiation therapy suffer angular limitations. In this way, this work aims to contribute to the development of a methodology of transmission quality control in vivo presenting a dose control technique using radiochromic film coupled to the headstock linear accelerator for radiotherapy applications to monitor conformational techniques and IMRT treatment. The quality control methodology developed in this work is based on obtaining the in vivo dose distribution of radiotherapy treatments with a radiochromic film EBT2, positioned on an acrylic stand, similar to a tray at a source-surface distance of 56.8 cm, coupled to the linear accelerator accessory holder during application of any treatment. It was subsequently performed a gama analysis for comparison of the dose distribution measured by the film with the expected dose distribution by the treatment planning system. The expected dose distribution was obtained in the coronal and central plane of a phantom, with similar dimensions to the acrylic stand and positioned on a source-surface distance of 100 cm as a result of the transfer of the plan in question. Based on the results presented in the conformational section, evaluating both, Monte Carlo simulation and irradiation results, it can be concluded that the difference between the distribution of the dose planning system, focus distance 100 cm detector, and the film, on distance of 56.8 cm, are small, and in this way it is feasible to create a methodology for dosimetry verification using radiochromic film coupled to the head of the accelerator. The proposed quality control in IMRT technique agreed with expected in 24 simulations of the 25 situations tested, showing only one different result, i.e., there was a 96% concordance with the expected. In this way, it can be concluded that the methodology proposed in this work is feasible for the in vivo quality control of radiation therapy treatments that use the conformational and IMRT treatment techniques, and also can be applied to the most modern radiotherapy techniques since, it does not offer difficulties with the angular displacement of the gantry.

A Radioterapia de lesões cerebrais próximas a estruturas críticas necessitam de uma alta precisão na localização e na dose. O rigor na liberação da dose deve ser acompanhado por um preciso controle da qualidade nos aparelhos que envolvam a prática. O comissionamento do sistema de planejamento consiste em averiguar e confirmar os cálculos realizados pelo sistema. Porém, mesmo com todo controle da qualidade no comissionamento, existem vários aspectos que podem influenciar na administração da dose no volume alvo, o que exige a necessidade de se fazer uma avaliação final, no ato do tratamento, in vivo. O objetivo deste trabalho é desenvolver uma técnica de dosimetria in vivo como parte de um programa de controle da qualidade em radioterapia estereotáxica. Na técnica de dosimetria in vivo, utilizaram-se segmentos de filme radiocrômico, com dimensões de 1x1 cm2, acoplados na área externa ao colimador formado por micro-lâminas, Moduleaf. Estes filmes foram inseridos na região central do feixe. Os filmes foram irradiados e calibrados para obtenção dos fatores campos, na configuração da técnica. Com estes dados foi elaborado um programa computacional, o qual calcula a densidade relativa que um filme deve adquirir quando submetido a uma exposição nesta configuração. Como a técnica de dosimetria in vivo usa os dados do TPS, validaram-se alguns parâmetros do comissionamento do TPS. Complementando o estudo da dosimetria in vivo foram avaliados cinco planos não co-planares, sendo o primeiro com 15 campos e os outros com 25 campos. Antes de iniciar o procedimento o segmento de filme era acoplado ao aparelho e após a execução do tratamento a densidade ótica era avaliada e comparada com a calculada pelo programa desenvolvido. No comissionamento, todas as dosimetrias relativas apresentaram diferenças percentuais menores que 2%, quando comparados os resultados medidos com os calculados pelo sistema de planejamento. No desenvolvimento da técnica de dosimetria in vivo, a diferença percentual média da verificação dosimétrica, no momento da irradiação, comparado com a calculada pela planilha foi de 1,5%, enquanto que a dosimetria absoluta aplicada ao controle da qualidade convencional foi aprovada com diferença percentual média de 2,5% e a função gama média encontrada foi de 97,9% dos pontos aprovados com critério de aceitação %=2% e D=2 mm. Logo, todos os dados estão em concordância com os limites estabelecidos pelo TRS-430. Desta forma, conclui-se que foi desenvolvida uma técnica de dosimetria in vivo como parte de um programa de controle da qualidade em radioterapia estereotáxica com filme radiocrômico, já que foram confirmados os parâmetros básicos do comissionamento do sistema de planejamento e a técnica foi validada com o controle de qualidade convencional nos cinco planos analisados. / Radiation therapy of brain lesions near critical structures requires a highly accurate location and dose. The accuracy in dose delivery should be accompanied by an accurate quality control in devices involving the practice. The commissioning of the planning system is to ascertain and confirm the calculations performed by the system, but even with all quality control in the commissioning, there are several aspects that may influence the dosing the target volume, which necessitates the need to make a final assessment at the time of treatment, in vivo. The objective of this work is to develop a technique for in vivo dosimetry as part of quality assurance in stereotactic radiotherapy. In vivo dosimetry technique, we used segments of film radiocrômico, with dimensions of 1x1 cm2, coupled to the external area formed by the micro-collimator blades, Moduleaf. These films were inserted in the central region of the beam. The films were irradiated and calibrated to obtain factors of fields in the configuration of the technique. With these data we designed a computer program which calculates the relative density of a film must acquire when subjected to an exposure in this setting. As the technique of in vivo dosimetry using data from the TPS, validated parameters are the commissioning of the TPS. Complementing the study of in vivo dosimetry were evaluated five non-coplanar plans, the first with 15 fields and the other with 25 fields. Before starting the procedure, the film segment was attached to the unit and after the treatment is the optical density was measured and compared with those calculated by the program developed. At commissioning, all presented on dosimetry percentage differences less than 2%, when comparing the measured results with those calculated by the planning system. In developing the technique of in vivo dosimetry, the mean percent difference dosimetry verification at the time of irradiation compared with the calculated by the sheet was 1.5%, while the absolute dosimetry applied to the conventional quality control has been approved as mean percent difference 2.5% and the gamma function mean was 97.9% of the points agreed with the acceptance criterion % = 2% and D = 2 mm. Therefore, all data are in agreement with the limits set by TRS-430. Thus, we conclude that we have developed a technique for in vivo dosimetry as part of a quality assurance in stereotactic radiotherapy radiocrômico film, since some parameters were confirmed to commissioning the planning system and the technique was validated with control quality standard in five plans analyzed.

<p>Proton beam therapy has shown great promise for cancer treatment due to its high precision in irradiating tumor volumes. However, due to the massive size and expense of the cyclotrons/synchrotrons needed to accelerate the protons, the widespread use of proton therapy is limited. Laser plasma accelerated (LPA) proton beams may be a potential alternative to conventional proton beams: by shooting an ultraintense, ultrashort pulsed laser at a thin target, a plasma sheath electric field may be formed with the capability of accelerating protons to potentially therapeutic energies in very short distances. In addition to accessibility, there is significant uncertainty in proton range in heterogeneous tissues. Thermoacoustic computed tomographic (TACT) imaging has the potential to provide <em>in vivo</em> dose imaging and range verification to address these uncertainties. TACT measures thermoacoustic waves generated from the absorbed dose and implements a 3D filtered backprojection to reconstruct volumetric images of the dose. The purpose of this thesis is to determine the feasibility of integrating LPA proton beams with thermoacoustic imaging into a novel image-guided small animal therapy platform as an early step towards clinical  translation to address the issues of accessibility and dosimetric spatial uncertainty. A Monte Carlo (MC) method is used to simulate an LPA proton beam with characteristics based on literature, thermoacoustic waves are simulated on a voxel-wise basis of the MC dose, and 3D filtered backprojection is used to reconstruct a volumetric image of the dose. In Specific Aim 1, the dependence of image accuracy on transducer array angular coverage is investigated; in Specific Aim 2, an iterative reconstruction algorithm is implemented to improve image accuracy through increased sampling of projection space when transducer array angular coverage is insufficient; and in Specific Aim 3, the detector sensitivity to dose is determined for several therapeutic endpoints. The work presented in this thesis not only demonstrates the feasibility of integrating LPA and thermoacoustic technologies but necessary design changes to realize a functional small animal platform.</p>

La radiothérapie externe représente une part importante du traitement conservateur du sein. Le calendrier classique consiste à délivrer une dose totale de 50 Gy en 25 fractions sur 5 semaines. Pour certaines catégories de femmes, une radiothérapie de 5 à 6 semaines, avec des transports longs et fréquents est parfois difficile à réaliser. La radiothérapie peropératoire (RIOP) permet de prévenir le risque de récidive locale dans le lit tumoral, et ne nécessite que quelques jours d’hospitalisation. Cette étude se concentre sur l’utilisation d'une source de rayons X miniaturisée de faible énergie (50kV). Après résection chirurgicale de la tumeur, un applicateur est inséré dans le lit tumoral et le système délivre une dose unique de 20 Gy à sa surface. Cependant, il n'y a pas de prescription personnalisée ni d'information sur la dose délivrée et ce point est contestable, car un texte officiel recommande une optimisation de la dose individuelle. Dans ce contexte, un calcul Monte Carlo permet d'évaluer avec précision la dose délivrée à la patiente en simulant le transport des particules. Cette thèse propose d'évaluer ce critère de dose absorbée le plus justement possible à partir d'une modélisation réaliste de la source de rayons X et de calculs de dose individuels à l'aide de simulations de Monte Carlo en prenant en compte les hétérogénéités tissulaires du sein. Des mesures dosimétriques in vivo viennent également confirmer les résultats de simulations. / External radiation therapy is an important part of breast conservative treatment. The conventional calendar is to deliver a total dose of 50 Gy in 25 fractions over 5 weeks. For certain categories of women, 5 to 6 weeks of radiotherapy, with long and frequent transport is sometimes difficult to achieve. Intra-operative radiotherapy (IORT) helps to prevent the risk of local recurrence in the tumor bed, and only requires a few days of hospitalization. This study focuses on the use of a miniaturized low energy X-ray source (50kV). After surgical resection of the tumor, an applicator is inserted into the tumor bed and the system delivers a single dose of 20 Gy on its surface. However, there is no custom prescription and this is questionable since an official text recommends optimizing the individual dose. In this context, a Monte Carlo calculation makes it possible to accurately assess the dose delivered to the patient by simulating the transport of particles. This thesis proposes to assess the absorbed dose criterion as accurately as possible from a realistic model of the X-ray source and individual dose calculations using Monte Carlo simulations taking into account the tissue heterogeneities of the breast. In vivo dosimetric measurements also confirm the results of simulations.

Accelerated protons are excellent candidates for treating several types of tumours. Such charged particles stop at a defined depth, where their ionisation density is maximum. As the dose deposit beyond this distal edge is very low, proton therapy minimises the damage to normal tissue compared to photon therapy. Nonetheless, inherent range uncertainties cast doubts on the irradiation of tumours close to organs at risk and lead to the application of conservative safety margins. This constrains significantly the potential benefits of proton over photon therapy and limits its ultimate aspirations. Prompt gamma rays, a by-product of the irradiation that is correlated to the dose deposition, are reliable signatures for the detection of range deviations and even for three-dimensional in vivo dosimetry. In this work, two methods for Prompt Gamma-ray Imaging (PGI) are investigated: the Compton camera (Cc) and the Prompt Gamma-ray Timing (PGT). Their applicability in a clinical scenario is discussed and compared. The first method aspires to reconstruct the prompt gamma ray emission density map based on an iterative imaging algorithm and multiple position sensitive gamma ray detectors. These are arranged in scatterer and absorber plane. The second method has been recently proposed as an alternative to collimated PGI systems and relies on timing spectroscopy with a single monolithic detector. The detection times of prompt gamma rays encode essential information about the depth-dose profile as a consequence of the measurable transit time of ions through matter. At Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and OncoRay, detector components are characterised in realistic radiation environments as a step towards a clinical Cc. Conventional block detectors deployed in commercial Positron Emission Tomography (PET) scanners, made of Cerium-doped lutetium oxyorthosilicate - Lu2SiO5:Ce (LSO) or Bismuth Germanium Oxide - Bi4Ge3O12 (BGO) scintillators, are suitable candidates for the absorber of a Cc due to their high density and absorption efficiency with respect to the prompt gamma ray energy range (several MeV). LSO and BGO block detectors are compared experimentally in clinically relevant radiation fields in terms of energy, spatial and time resolution. On a different note, two BGO block detectors (from PET scanners), arranged as the BGO block Compton camera (BbCc), are deployed for simple imaging tests with high energy prompt gamma rays produced in homogeneous Plexiglas targets by a proton pencil beam. The rationale is to maximise the detection efficiency in the scatterer plane despite a moderate energy resolution. Target shifts, increase of the target thickness and beam energy variation experiments are conducted. Concerning the PGT concept, in a collaboration among OncoRay, HZDR and IBA, the first test at a clinical proton accelerator (Westdeutsches Protonentherapiezentrum Essen) with several detectors and heterogeneous phantoms is performed. The sensitivity of the method to range shifts is investigated, the robustness against background and stability of the beam bunch time profile is explored, and the bunch time spread is characterised for different proton energies. With respect to the material choice for the absorber of the Cc, the BGO scintillator closes the gap with respect to the brighter LSO. The reason behind is the high energies of prompt gamma rays compared to the PET scenario, which increase significantly the energy, spatial and time resolution of BGO. Regarding the BbCc, shifts of a point-like radioactive source are correctly detected, line sources are reconstructed, and one centimetre proton range deviations are identified based on the evident changes of the back projection images. Concerning the PGT experiments, for clinically relevant doses, range differences of five millimetres in defined heterogeneous targets are identified by numerical comparison of the spectrum shape. For higher statistics, range shifts down to two millimetres are detectable. Experimental data are well reproduced by analytical modelling. The Cc and the PGT are ambitious approaches for range verification in proton therapy based on PGI. Intensive detector characterisation and tests in clinical facilities are mandatory for developing robust prototypes, since the energy range of prompt gamma rays spans over the MeV region, not used traditionally in medical applications. Regarding the material choice for the Cc: notwithstanding the overall superiority of LSO, BGO catches up in the field of PGI. It can be considered as a competitive alternative to LSO for the absorber plane due to its lower price, higher photoabsorption efficiency, and the lack of intrinsic radioactivity. The results concerning the BbCc, obtained with relatively simple means, highlight the potential application of Compton cameras for high energy prompt gamma ray imaging. Nevertheless, technical constraints like the low statistics collected per pencil beam spot (if clinical currents are used) question their applicability as a real-time and in vivo range verification method in proton therapy. The PGT is an alternative approach, which may have faster translation into clinical practice due to its lower price and higher efficiency. A proton bunch monitor, higher detector throughput and quantitative range retrieval are the upcoming steps towards a clinically applicable prototype, that may detect significant range deviations for the strongest beam spots. The experimental results emphasise the prospects of this straightforward verification method at a clinical pencil beam and settle this novel approach as a promising alternative in the field of in vivo dosimetry. / Beschleunigte Protonen sind ausgezeichnete Kandidaten für die Behandlung von diversen Tumorarten. Diese geladenen Teilchen stoppen in einer bestimmten Tiefe, bei der die Ionisierungsdichte maximal ist. Da die deponierte Dosis hinter der distalen Kante sehr klein ist, minimiert die Protonentherapie den Schaden an normalem Gewebe verglichen mit der Photonentherapie. Inhärente Reichweitenunsicherheiten stellen jedoch die Bestrahlung von Tumoren in der Nähe von Risikoorganen in Frage und führen zur Anwendung von konservativen Sicherheitssäumen. Dadurch werden die potentiellen Vorteile der Protonen- gegenüber der Photonentherapie sowie ihre letzten Ziele eingeschränkt. Prompte Gammastrahlung, ein Nebenprodukt der Bestrahlung, welche mit der Dosisdeposition korreliert, ist eine zuverlässige Signatur um Reichweitenunterschiede zu detektieren und könnte sogar für eine dreidimensionale in vivo Dosimetrie genutzt werden. In dieser Arbeit werden zwei Methoden für Prompt Gamma-ray Imaging (PGI) erforscht: die Compton-Kamera (CK) und das Prompt Gamma-ray Timing (PGT)-Konzept. Des Weiteren soll deren Anwendbarkeit im klinischen Szenario diskutiert und verglichen werden. Die erste Methode strebt nach der Rekonstruktion der Emissionsdichtenverteilung der prompten Gammastrahlung und basiert auf einem iterativen Bildgebungsalgorithmus sowie auf mehreren positionsempfindlichen Detektoren. Diese werden in eine Streuer- und Absorberebene eingeteilt. Die zweite Methode ist vor Kurzem als eine Alternative zu kollimierten PGI Systemen vorgeschlagen worden, und beruht auf dem Prinzip der Zeitspektroskopie mit einem einzelnen monolithischen Detektor. Die Detektionszeiten der prompten Gammastrahlen beinhalten entscheidende Informationen über das Tiefendosisprofil aufgrund der messbaren Durchgangszeit von Ionen durch Materie. Am Helmholtz-Zentrum Dresden-Rossendorf (HZDR) und OncoRay werden Detektorkomponenten in realistischen Strahlungsumgebungen als ein Schritt zur klinischen CK charakterisiert. Konventionelle Blockdetektoren, welche in kommerziellen Positronen-Emissions-Tomographie (PET)-Scannern zum Einsatz kommen und auf Cer dotiertem Lutetiumoxyorthosilikat - Lu2SiO5:Ce (LSO) oder Bismutgermanat - Bi4Ge3O12 (BGO) Szintillatoren basieren, sind geeignete Kandidaten für den Absorber einer CK wegen der hohen Dichte und Absorptionseffizienz im Energiebereich von prompten Gammastrahlen (mehrere MeV). LSO- und BGO-Blockdetektoren werden in klinisch relevanten Strahlungsfeldern in Bezug auf Energie-, Orts- und Zeitauflösung verglichen. Weiterhin werden zwei BGO-Blockdetektoren (von PET-Scannern), angeordnet als BGO Block Compton-Kamera (BBCK), benutzt, um die Bildgebung von hochenergetischen prompten Gammastrahlen zu untersuchen, die in homogenen Plexiglas-Targets durch einen Protonen-Bleistiftstrahl emittiert werden. Die Motivation hierfür ist, die Detektionseffizienz der Streuerebene zu maximieren, wobei jedoch die Energieauflösung vernachlässigt wird. Targetverschiebungen, sowie Änderungen der Targetdicke und der Teilchenenergie werden untersucht. In einer Kollaboration zwischen OncoRay, HZDR and IBA, wird der erste Test des PGT-Konzepts an einem klinischen Protonenbeschleuniger (Westdeutsches Protonentherapiezentrum Essen) mit mehreren Detektoren und heterogenen Phantomen durchgeführt. Die Sensitivität der Methode hinsichtlich Reichweitenveränderungen wird erforscht. Des Weiteren wird der Einfluss von Untergrund und Stabilität des Zeitprofils des Strahlenbündels untersucht, sowie die Zeitverschmierung des Bündels für verschiedene Protonenenergien charakterisiert. Für die Materialauswahl für den Absorber der CK ergibt sich, dass sich BGO dem lichtstärkeren LSO Szintillator angleicht. Der Grund dafür sind die höheren Energien der prompten Gammastrahlung im Vergleich zum PET Szenario, welche die Energie-, Orts- und Zeitauflösung von BGO stark verbessern. Anhand von offensichtlichen Änderungen der Rückprojektionsbilder zeigt sich, dass mit der BBCK Verschiebungen einer punktförmigen radioaktiven Quelle erfolgreich detektiert, Linienquellen rekonstruiert und Verschiebungen der Protonenreichweite um einen Zentimeter identifiziert werden. Für die PGT-Experimente können mit einem einzigen Detektor Reichweitenunterschiede von fünf Millimetern für definierte heterogene Targets bei klinisch relevanten Dosen detektiert werden. Dies wird durch den numerischen Vergleich der Spektrumform ermöglicht. Bei größerer Ereigniszahl können Reichweitenunterschiede von bis zu zwei Millimetern detektiert werden. Die experimentellen Daten werden durch analytische Modellierung wiedergegeben. Die CK und das PGT-Konzept sind ambitionierte Ansätze zur Verifizierung der Reichweite in der Protonentherapie basierend auf PGI. Intensive Detektorcharakterisierung und Tests an klinischen Einrichtungen sind Pflicht für die Entwicklung geeigneter Prototypen, da der Energiebereich prompter Gammastrahlung sich über mehrere MeV erstreckt, was nicht dem Normbereich der traditionellen medizinischen Anwendungen entspricht. Im Bezug auf die Materialauswahl der CK wird ersichtlich, dass BGO trotz der allgemeinen Überlegenheit von LSO für die Anwendung im Bereich PGI aufholt. Wegen des niedrigeren Preises, der höheren Photoabsorptionseffizienz und der nicht vorhandenen Eigenaktivität erscheint BGO als eine konkurrenzfähige Alternative für die Absorberebene der CK im Vergleich zu LSO. Die Ergebnisse der BBCK, welche mit relativ einfachen Mitteln gewonnen werden, heben die potentielle Anwendung von Compton-Kameras für die Bildgebung prompter hochenergetischer Gammastrahlen hervor. Trotzdem stellen technische Beschränkungen wie die mangelnde Anzahl von Messereignissen pro Bestrahlungspunkt (falls klinische Ströme genutzt werden) die Anwendbarkeit der CK als Echtzeit- und in vivo Reichweitenverifikationsmethode in der Protonentherapie in Frage. Die PGT-Methode ist ein alternativer Ansatz, welcher aufgrund der geringeren Kosten und der höheren Effizienz eine schnellere Umsetzung in die klinische Praxis haben könnte. Ein Protonenbunchmonitor, höherer Detektordurchsatz und eine quantitative Reichweitenrekonstruktion sind die weiteren Schritte in Richtung eines klinisch anwendbaren Prototyps, der signifikante Reichweitenunterschiede für die stärksten Bestrahlungspunkte detektieren könnte. Die experimentellen Ergebnisse unterstreichen das Potential dieser Reichweitenverifikationsmethode an einem klinischen Bleistiftstrahl und lassen diesen neuartigen Ansatz als eine vielversprechende Alternative auf dem Gebiet der in vivo Dosimetrie erscheinen.

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.