New methods of high dose delivery, such as intensity modulated radiation therapy (IMRT), stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS), hadron therapy, tomotherapy, etc., all make use of a few large fractions. To improve these treatments, there are three main directions: (i) improving physical dose distribution, (ii) optimizing radiosurgery dose-time scheme and (iii) modifying dose response of tumors or normal tissues. Different radiation modalities and systems have been developed to deliver the best possible physical dose to the target while keeping radiation to normal tissue minimum. Although applications of radiobiological findings to clinical practice are still at an early stage, many studies have shown that   sublethal radiation damage repair kinetics plays an important role in tissue response to radiation. The purpose of the present thesis is to show how the above-mentioned directions could be used to improve treatment outcomes with special interest in radiation modalities and dose-time scheme, as well as radiobiological modeling. Also for arteriovenous malformations (AVM), the possible impact of AVM network angiostructure in radiation response was studied. / Nya och förbättrade metoder för precisionsbestrålning, såsom intensitetsmodulerad strålbehandling (IMRT), stereotaktisk strålbehandling (SRT), stereotaktisk strålkirurgi (SRS) eller hadronterapi etc., gör det möjligt att leverera behandlingen i ett fåtal fraktioner med höga doser. Dessa behandlingmetoder kan ytterligare förbättras genom att (i) förbättra den fysikaliska dosfördelningen, (ii) optimera dosrater och fraktioneringsscheman eller (iii) modifiera dosresponsen hos tumörer eller normalvävnad. Olika strålmodaliteter och behandlingssystem har tagits fram för att kunna leverera bästa möjliga fysikaliska dosfördelning till targetvolymen samtidigt som dosen till frisk vävnad hålls så låg som möjligt. Även om användandet av radiobiologisk kunskap och modeller i klinisk rutin ännu är i sin linda så visar många studier att kinetiken för subletal reparation av strålskador har stor betydelse för strålresponsen. Syftet med denna avhandling är att visa hur dessa olika utvecklingsvägar kan användas för att förbättra behandlingsresultatet speciellt genom att studera vald strålmodalitet, dosrat och fraktioneringsschema samt radiobiologisk modellering. För arteriovenösa missbildningar (AVM) har även  studerats hur strukturen hos angionätverket påverkar strålresponsen. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.</p>

No description available.

INTRODUCTION: Cancers of the gastrointestinal tract are the second most prevalent malignancy with 289,610 new cases last year and the second most common cause of cancer-related death with 150,000 deaths last year in the United States. Prognosis for patients with these malignancies is poor and worsens significantly once the cancer has metastasized to the brain. We evaluated the outcome of patients following Stereotactic Radiosurgery (SRS) for brain metastases (BM) in individuals with GI cancers to identify safety and effectivity of treatment and we assessed prognostic factors that affect tumor control and survival. OBJECTIVES: By the conclusion of this session, participants should be able to: 1) Identify an effective treatment for brain metastases from GI cancers in terms of increasing survival; 2) Identify which treatment provides the best local and distant control of CNS disease; 3) Discuss the effects of different prognostic factors on local control and survival. METHODS: This is a retrospective analysis of 58 brain metastases from 18 consecutive patients who underwent SRS treatment at BIDMC between 2006 and 2013. 11/18 patients underwent prior microsurgical resection for their metastases and 3/18 patients had undergone Whole Brain Radiation Therapy (WBRT). Overall Survival (OS), Local Control (LC), Distal control (DC), and prognostic factors such as age, number of brain metastases (BM), Karnofsky Performance Status (KPS), Recursive Partition Analysis (RPA) and Disease Specific Graded Prognostic Assessment (Ds-GPA) class were evaluated. RESULTS: The median overall survival (mOS) for the entire cohort was 14 months after the diagnosis of BM. The mOS for patients receiving only SRS, Surgical Resection + SRS, and WBXRT + SRS were 8 months, 18 months, and 13 months respectively. The difference in overall survival between treatment groups was not found to be statistically significant. Increasing number of BM was a factor shown to negatively influence survival. Local control was achieved in 55% of lesions after SRS, and in 75% of lesions that were surgically resected followed by SRS boost to the resection cavity. The difference in local control between SRS alone vs. Surgery + SRS was found to be statistically significant (p = 0.013). CONCLUSION: With a higher overall survival and significantly better local control rates, Surgery followed by SRS boost to the resection cavity should be considered as the treatment of choice in this specific subgroup of cancer patients as this study shows that they benefit from this more aggressive treatment option.

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A radiocirugia estereotáxica é uma técnica que fornece altas doses de radiação utilizando campos pequenos para conformação da dose no volume alvo do tratamento. Devido à complexidade desta técnica torna-se necessária a verificação da distribuição de dose no volume de tratamento. Neste trabalho, as distribuições tridimensionais (3D) de doses de casos clínicos de neoplasias cranianas foram estudadas utilizando-se um objeto simulador de cabeça. A reconstrução das distribuições de doses nos volumes alvo e nas regiões adjacentes a estes foram avaliadas com o código de simulação PENELOPE, o dosímetro MAGIC-f gel e com o sistema de planejamento iPlan. Filmes radiocrômicos também foram empregados para a determinação das distribuições de dose em planos do tratamento. As respostas obtidas com as ferramentas dosimétricas utilizadas foram analisadas através de distribuições de índices gama, comparando-se os mapas centrais das distribuições de dose obtidas com as quatro ferramentas dosimétricas utilizadas. Usando-se critérios de tolerância de 3% e 3mm, a análise realizada na região da prescrição de dose (isodoses de 95%) mostrou-se equivalente para todas as ferramentas dosimétricas utilizadas; resultado diferente foi observado para isodoses menores, com uma equivalência máxima de 76,5%. As distribuições volumétricas, obtidas através do PENELOPE, MAGIC-f gel e o iPlan, foram comparadas, ainda, através dos histogramas dose-volume, para cada caso estudado, mostrando que 95% da dose absorvida relativa encontra-se dentro do volume alvo para todos os planos estudados. A probabilidade de controle tumoral, TCP, foi avaliada para os casos de radiocirurgia estudados, a partir das distribuições volumétricas de dose, resultando em uma probabilidade de controle tumoral máxima de 72%, para todos os casos, conforme o modelo matemático de TCP utilizado. Das comparações realizadas pode-se inferir que o dosímetro MAGIC-f gel e o código de simulação PENELOPE-Monte Carlo podem ser utilizados para determinar as distribuições de dose em 3D para a técnica de radiocirurgia estereotáxica. Essas ferramentas dosimétricas podem, dessa forma, auxiliar no comissionamento de unidades de terapia e em verificações 3D de doses do tratamento dos pacientes, permitindo avaliações dentro e ao redor do volume alvo e podendo se tornar ferramentais de rotina nos serviços de radioterapia. / Stereotactic radiosurgery is a technique which delivers high radiation doses using small fields to conform the absorbed dose into the target volume. Due to the complexity of this technique it is necessary to verify the dose distribution in the treatment volume. Thus, in this study the three-dimensional (3D) dose distributions of selected clinical cases of cranial tumors were obtained using a head phantom. The the dose distributions of target volumes and adjacent regions were evaluated with PENELOPE Monte Carlo simulation code, MAGIC-f dosimeter and iPlan® treatment planning system. Radiochromic films were also used to determine the dose distribution on selected plans of the treatment. The obtained results for the proposed dosimetric tools were analyzed by the gamma index distributions, comparing the maps of the central dose distributions obtained with the four dosimetric tools. Using the dose criteria of 3% in 3 mm, the gamma index test showed equivalence in the region of dose prescription (95% isodose) and a different result was observed for lower isodoses, with maximum accordance of 76.5%. The volumetric dose distributions obtained with PENELOPE, MAGIC-f and iPlan were also compared using the dose-volume histograms for each studied case, showing that 95% of the absorbed dose yield within the target volume. The tumor control probability, TCP, was evaluated for the studied radiosurgery cases, from the dose distributions-volumetric, resulting in a maximum probability of tumor control of 72% for all cases, for the used mathematical model of TCP. From the results it can be inferred that the MAGIC-f gel dosimeter and the PENELOPE Monte Carlo simulation code can be used to determine 3D dose distributions for stereotactic radiosurgery. These dosimetric tools can assist the commissioning of treatment units and 3D dose verifications of patients treatments, allowing assessments in and around the target volume and may become routine in radiotherapy services.

A radiocirugia estereotáxica é uma técnica que fornece altas doses de radiação utilizando campos pequenos para conformação da dose no volume alvo do tratamento. Devido à complexidade desta técnica torna-se necessária a verificação da distribuição de dose no volume de tratamento. Neste trabalho, as distribuições tridimensionais (3D) de doses de casos clínicos de neoplasias cranianas foram estudadas utilizando-se um objeto simulador de cabeça. A reconstrução das distribuições de doses nos volumes alvo e nas regiões adjacentes a estes foram avaliadas com o código de simulação PENELOPE, o dosímetro MAGIC-f gel e com o sistema de planejamento iPlan. Filmes radiocrômicos também foram empregados para a determinação das distribuições de dose em planos do tratamento. As respostas obtidas com as ferramentas dosimétricas utilizadas foram analisadas através de distribuições de índices gama, comparando-se os mapas centrais das distribuições de dose obtidas com as quatro ferramentas dosimétricas utilizadas. Usando-se critérios de tolerância de 3% e 3mm, a análise realizada na região da prescrição de dose (isodoses de 95%) mostrou-se equivalente para todas as ferramentas dosimétricas utilizadas; resultado diferente foi observado para isodoses menores, com uma equivalência máxima de 76,5%. As distribuições volumétricas, obtidas através do PENELOPE, MAGIC-f gel e o iPlan, foram comparadas, ainda, através dos histogramas dose-volume, para cada caso estudado, mostrando que 95% da dose absorvida relativa encontra-se dentro do volume alvo para todos os planos estudados. A probabilidade de controle tumoral, TCP, foi avaliada para os casos de radiocirurgia estudados, a partir das distribuições volumétricas de dose, resultando em uma probabilidade de controle tumoral máxima de 72%, para todos os casos, conforme o modelo matemático de TCP utilizado. Das comparações realizadas pode-se inferir que o dosímetro MAGIC-f gel e o código de simulação PENELOPE-Monte Carlo podem ser utilizados para determinar as distribuições de dose em 3D para a técnica de radiocirurgia estereotáxica. Essas ferramentas dosimétricas podem, dessa forma, auxiliar no comissionamento de unidades de terapia e em verificações 3D de doses do tratamento dos pacientes, permitindo avaliações dentro e ao redor do volume alvo e podendo se tornar ferramentais de rotina nos serviços de radioterapia. / Stereotactic radiosurgery is a technique which delivers high radiation doses using small fields to conform the absorbed dose into the target volume. Due to the complexity of this technique it is necessary to verify the dose distribution in the treatment volume. Thus, in this study the three-dimensional (3D) dose distributions of selected clinical cases of cranial tumors were obtained using a head phantom. The the dose distributions of target volumes and adjacent regions were evaluated with PENELOPE Monte Carlo simulation code, MAGIC-f dosimeter and iPlan® treatment planning system. Radiochromic films were also used to determine the dose distribution on selected plans of the treatment. The obtained results for the proposed dosimetric tools were analyzed by the gamma index distributions, comparing the maps of the central dose distributions obtained with the four dosimetric tools. Using the dose criteria of 3% in 3 mm, the gamma index test showed equivalence in the region of dose prescription (95% isodose) and a different result was observed for lower isodoses, with maximum accordance of 76.5%. The volumetric dose distributions obtained with PENELOPE, MAGIC-f and iPlan were also compared using the dose-volume histograms for each studied case, showing that 95% of the absorbed dose yield within the target volume. The tumor control probability, TCP, was evaluated for the studied radiosurgery cases, from the dose distributions-volumetric, resulting in a maximum probability of tumor control of 72% for all cases, for the used mathematical model of TCP. From the results it can be inferred that the MAGIC-f gel dosimeter and the PENELOPE Monte Carlo simulation code can be used to determine 3D dose distributions for stereotactic radiosurgery. These dosimetric tools can assist the commissioning of treatment units and 3D dose verifications of patients treatments, allowing assessments in and around the target volume and may become routine in radiotherapy services.

The Leksell Gamma Knife® is an instrument designed for high precision treatment of tumours and lesions located in the brain and upper spine. Today, the radioactive cobalt-60 sources can only move linearly along the radiation unit, but the machine could be modified to include rotational motion as well. We extend an existing linear programming approach to inverse planning for the Gamma Knife by examining the benefits from rotational degrees of freedom. The improvements offered from rotations are limited, but easy to make use of. We investigate the model in four patient cases, and find that an upper bound on the improvement of the optimization cost function is between 4.5% and 7.0% depending on case. With a total of four angles distributed uniformly over a 45 degree interval, one can in each case achieve a solution that performs up to within 1% of this bound. The average maximal improvements in terms of clinical metrics are 0.5% selectivity and 1.9% gradient index, at the cost of 5.9% worse beam-on time. No statistically significant change in coverage is found. A dynamic model based on column generation is proposed, which allows treatment during constant velocity angular motion and can achieve practically the same plan quality as the model with uniformly distributed angles at a significantly lower problem size. A similar algorithm can be designed to locate the most effective angles in a non-uniform manner that achieves better plans with fewer added rotational degrees of freedom. Trade-offs between memory and solution times are used to successively reduce the RAM occupation by around 90% and make significantly larger models computationally feasible to solve. A voxel clustering approach with emphasis on surface voxels, adapted to the radiosurgical framework, can significantly reduce the problem size while still producing competitive plans. / Strålkniven Leksell Gamma Knife® är ett instrument designat för högprecisionsbestrålning av tumörer och lesioner i hjärnan och övre delen av ryggraden. Idag kan de radioaktiva källorna endast förflyttas linjärt under behandlingen, men maskinen skulle kunna modifieras för att även tillåta rotationsrörelser. Vi utvidgar ett ramverk för inversplanering, formulerat som ett linjär-programmeringsproblem, genom att undersöka fördelarna med nya rotationsfrihetsgrader. Förbättringarna som rotationer möjliggör är begränsade, men kan relativt enkelt tas till vara. Vi undersöker de potentiella förändringarna i fyra patientfall och finner att den övre gränsen av förbättringarna för målfunktionsvärdet i optimeringsproblemet är mellan 4.5% och 7.0% beroende på fall. Genom att tillåta rotation av källorna till fyra jämnt fördelade vinklar över 45 grader kan man i samtliga fall hitta en lösning som är inom 1% från det bästa målfunktionsvärdet. De genomsnittliga förbättringarna i form av kliniska metriker är 0.5% selektivitet och 1.9% gradient-index, dock på bekostnad av en försämring av bestrålningstiden med 5.9%. Ingen tydlig förändring av täckningen kunde påvisas. En modell baserad på kolumngenerering, som tillåter behandling under rotation av kollimator-kroppen med konstant hastighet, föreslås. I denna modell kan praktiskt taget lika bra lösningar uppnås som för likformigt fördelade vinklar, men med betydligt mindre problemstorlek. En liknande algoritm kan lokalisera de mest effektiva vinklarna och åstadkomma samma plankvalitet med färre, men olikformt fördelade, rotationsfrihetsgrader. RAM-användningen kan reduceras med cirka 90% genom avvägningar mellan minne och beräknings-tider, vilket möjliggör lösning av probleminstanser som tidigare var beräkningsmässigt omöjliga. Klustringsmetoder av voxlar anpassade till strålkniven kan minska problemstorleken betydelsefullt medan de resulterande behandlingsplanerna är fortsatt konkurrenskraftiga.

Le Cyberknife (Accuray, Sunnyvale, CA) est un appareil de radiochirurgie stéréotaxique sans cadre. Il a été développé pour administrer de fortes doses dans des volumes restreints. Aussi, pour obtenir une conformation optimale de traitement, des champs circulaires de petites dimensions sont utilisés (\phi = 0,5 à 6 cm). L'étude dosimétrique de ces petits champs doit être menée selon de nouveaux standards puisque ceux-ci échappent aux définitions du TG-51. L'objectif de ce projet est d'implanter une plateforme de calcul de dose de type Monte Carlo pour le CyberKnife en clinique. Il s'articule autour de deux réalisations principales. Tout d'abord, une caractérisation dosimétrique du modèle Monte Carlo de l'accélérateur linéaire du CyberKnife a été menée à travers des simulations Monte Carlo générées par le moteur de EGSnrc. Cette étude est basée sur la caractérisation de la réponse d'un détecteur à un champ de type CK à partir de simulations EGS_chamber. Cette approche permet de prendre en compte l'impact du détecteur sur les mesures expérimentales. Cet aspect est d'autant plus important que le modèle Monte Carlo de l'accélérateur est validé à partir de mesures expérimentales. Les résultats obtenus montrent une bonne concordance, <1% ou 1 mm, entre les mesures expérimentales et les données de simulations pour les grands champs. Pour les champs de diamètre < 12,5 mm, le modèle est moins exact et une correction est appliquée pour atteindre une différence de <1% ou 1 mm. Deuxièmement, ce modèle validé du CK a été implanté dans un cadre de calcul Monte Carlo complet. Une plateforme de calcul dédiée aux calculs Monte Carlo, WebTPS, a été adaptée aux calculs de dose CK. Cette plateforme reçoit les données relatives au plan de traitement et lance des calcul EGSnrc sur un superordinateur. Cette approche tend à réduire les approximations lors de l'évaluation dosimétrique de plans de traitements cliniques. Une incertitude inférieure à 1% peut être atteinte en deux heures de calcul. Ce projet a donc pour objectif de développer une référence clinique pour le calcul de dose dans le cadre de la radiochirurgie stéréotaxique. L'outil WebTPS pourrait être particulièrement utile en clinique, l'algorithme de calcul de dose du CK étant limité dans plusieurs situations de traitement. / Purpose: The scope of this study is to implement a clinical Monte Carlo dose calculation system based on the EGSnrc engine. This web-based tool will be mostly used to evaluate clinical treatment plans in highly heterogeneous phantoms. Methods: The Monte Carlo calculation tool is based on the DOSXYZnrc user code. The platform automatically converts CyberKnife clinical plan to the user code input files. Phantoms can be created from HU to ED curves or by manually assigning material using medical contours. Parallel computation is made on a Compute Canada high-performance cluster to reduce simulation time. A Monte Carlo CyberKnife model is built on BEAMnrc user code using the manufacturer specifications. Simulated and experimental data is compared to estimate the electron beam parameters. The beam energy estimation is based on percent depth dose (PDD) comparison while the full width at half max (FWHM) is validated by output factor (OF) and off-axis ratio (OAR). An EGS_chamber model of the PTW60012 diode is used in the OF calculation. A set of phase-spaces is generated from the optimal model and for each collimator to calculate dose contribution from each incident beam. Results: The linac model optimisation yielded a 0.5% PDD agreement between experimental and simulation data, and a 0.5% or 1 mm for OAR. DOSxyz simulation of full treatment plan, based on the preliminary CyberKnife model, were achieved. Total Monte Carlo dose calculation have been achieved for heterogeneous phantoms. Uncertainty under 1% can be achieved for less than 2 hour of computing time. However, computing time estimation is nontrivial due to its dependence on cluster availability. Conclusion: This work aims to develop a suitable tool for reference plan dose calculation. This web-based tool would be used in several clinical and research applications where the CyberKnife embedded ray-tracing algorithm would show significant limitations. Because it is destined to a clinical use, the whole dose calculation system will be rigorously validated. / Le travail de modélisation a été réalisé à travers EGSnrc, un logiciel développé par le Conseil National de Recherche Canada.