In this project we introduced a spatial frequency-based objective function for optimization of dose distributions used in spatially fractionated radiotherapy (also known as grid therapy). Several studies indicate that tissues can tolerate larger mean doses of radiation if the dose is delivered heterogeneously or to a partial volume of the organ. The objective function rewards heterogeneous dose distributions in the collaterally irradiated healthy tissues and is based on the concept of a maximum stem-cell migration distance. The stem-cell depletion hypothesis stipulates that damaged tissues can be repopulated by nearby surviving stem-cells within a critical volume outlined by the maximum migration distance. Proton grid therapy dose distributions were calculated to study the viability of our spatial frequency-based objective function. These were computed analytically with a proton pencil beam dose kernel. A multi-slit collimator placed flush against the surface of a water phantom defined the entrance fluence. The collimator geometry was described by two free parameters: the slit width and the number of slits within a specified field width. Organs at risk (OARs) and a planning target volume (PTV) were defined. Two dose constraints were set on the PTV and objective function values were computed for the OARs. The objective function measures the high-frequency content of a masked dose distribution, where the distinction between low- and high frequencies was made based on a characteristic distance. Out of the feasible solutions, the irradiation geometry that produced the maximum objective function value was selected as the optimal solution. With the spatial frequency-based objective function we were able to find, by brute-force search, unique optimal solutions to the constrained optimization problem. The optimal solutions were found on the boundary of the solution space. The objective function can be applied directly to arbitrarily shaped regions of interest and to dose distributions produced by multiple field angles. The next step is to implement the objective function in an optimization environment of a commercial treatment planning system (TPS).

[Truncated abstract] Therapeutic Radiation has been used for the treatment of cancer and other diseases for nearly a century. Over the past 20 years, Hyperbaric Oxygen Treatment (HBOT) has been used to assist wound healing in the prevention and treatment of the more severe complications associated with the side effects of Therapeutic Radiation Treatment (TRT). The use of HBOT is based on the premise that increased oxygen tissue tension aids wound healing by increasing the hypoxic gradient and stimulating angiogenesis and fibroblast differentiation. As it takes up to 6 months for a hypoxic state to develop in treated tissue, following radiation treatment, current recommendations for HBOT state that it is not effective until after this time. During this 6 month period, immediately following TRT, many specialized tissues in or adjacent to the field of irradiation, such as salivary glands and bone, are damaged due to a progressive thickening of arteries and fibrosis, and these tissues are never replaced. Currently, HBOT is used to treat the complications of TRT, but it would be far better if they could be prevented . . . In summary, this experimental model has fulfilled its prime objective of demonstrating that HBOT is effective in reducing the long-term side effects of therapeutic radiation treatment in normal tissue, when given one week after the completion of the radiation treatment and statistically disproves the Null Hypothesis that there is no difference in the incidence of postoperative complications or morbidity of TRT when 20 intermittent daily HBOT are started one week after completion of TRT. This project provides an extensive description of the histological process and also proposes a hypothesis for the molecular events that may be taking place.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser. I publikationen felaktig serieuppgift: Linköping studies in health sciences ; 989.

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.

5 à 15% des 175 000 patients traités par radiothérapie (RT) chaque année sont exposés à une toxicité considérée comme « inhabituelle » pouvant entraîner des séquelles parfois graves. Les techniques innovantes de photonthérapie apportent une solution balistique pertinente mais inappropriée pour certaines tumeurs ou certains patients. Deux approches permettent d'entrevoir des solutions à ces situations. 1- Contribution au développement de l'hadronthérapie par ions carbone : Ces particules possèdent une masse et une charge qui leur confèrent un avantage balistique et biologique particulièrement intéressant. Le caractère rare des tumeurs éligibles et le très faible nombre de centres n'ont pas permis, ou justifié, à ce jour la réalisation d'études comparatives randomisées afin d'en évaluer le service rendu. Via le projet FP7 ULICE, nous avons intégré et animé plusieurs groupes à l'échelle nationale et internationale. Nous avons directement produit des procédures unifiées en terme d'immobilisation, de recueil des données élémentaires, de structuration protocolaire et de transformation des données en métadonnées échangeables. Nous avons proposé des concepts originaux permettant de décrire la dose prescrite et les volumes d'intérêt, au-delà du concept réducteur d'EBR. 2- Un nouveau biomarqueur de radiosensibilité individuelle (RSI). L'identification des patients les plus à risque de développer les réactions les plus sévères reste un enjeu majeur. Aucun test de RSI ne s'impose comme gold standard. A partir de primocultures fibroblastiques issues de patients ayant présenté un profil de toxicité inhabituel à la RT, le taux de cassures double brins résiduelles à 24h estimé par immunofluorescence indirecte (marqueur γH2AX) a permis de définir 3 groupes de RSI. Toutefois ce seul marqueur n'est pas assez robuste. Le délai de transit cyto-nucléaire de la protéine ATM semble affiner notre classification. Un nouveau modèle mécanistique a ainsi pu être développé / 5 to 15% of the 175,000 patients treated with radiation therapy (RT) annually are exposed to toxicity considered "unusual" that can lead to serious sequelae. Innovative photon RT techniques provide relevant but inappropriate ballistic solution for certain tumors or certain patients. Two approaches guide solutions to these situations.1- Contribution to the development of carbon ion RT. These particles possess a mass and a charge that give them particularly interesting ballistics and biological properties. The rarity of eligible tumors and the low care offer have failed conducting randomized controlled trials to evaluate its cost-effectiveness. Throughout the FP7-ULICE project, we directly produced standard operating procedures in terms of basic data collection, protocol structuring and processing of metadata. We proposed original concepts to describe and report the dose and volume of interest, beyond the restricted concept of RBE. 2- A novel biomarker of individual radiosensitivity (IRS). The identification of the patients the most at risk of developing the most severe reactions remains a major challenge. There is no gold standard in the field of IRS assays.From fibroblasts primocultures sampled from patients with an unusual toxicity, the number of residual DNA double-stand breaks 24h after radiation and estimated by indirect immunofluorescence (marker γH2AX) allows to identify three groups of IRS. However this single marker is not robust enough. The delay of ATM nucleoshuttling appears to refine our classification. A new mechanistic model has been developed

En radiothérapie externe, le traitement est administré au patient avec une séance chaque jour en utilisant le traitement établi en amont et répété jusqu’à la fin du traitement. La planification du traitement est établie par un système de planification du traitement (TPS) qui utilise des informations basées sur l’anatomie du patient (CT, IRM, TEP) et un calcul de dose. L'intégration aux unités de traitement des dispositifs d´ imagerie embarquée peuvent être utilisées pour vérifier la position du patient et son anatomie (dispositif d’imagerie Portal Électronique - EPID-, tomodensitométrie à faisceau conique - CBCT -). L'objectif principal est de fournir une solution robuste pour la routine afin de contrôler la dose délivrée au patient avec la dose prévue établie à partir du TPS. La première partie de ce travail consiste à intégrer une comparaison d'images EPID pour chaque fraction par rapport à la fraction planifiée (images CT) en acceptant, rejetant ou ignorant la différence de position et de niveau de dose du patient selon une tolérance seuil définie par l’utilisateur. La deuxième partie consiste à utiliser l´ imagerie volumique embarquée pour reconstruire la dose délivrée fraction par fraction en réalisant un calcul de dose. Avec la dose reçue par le patient jour après jour, sur la base de nouveaux indicateurs, il est possible d’établir une traçabilité permettant d’identifier les déviations et d’évaluer la qualité du traitement.Pour conclure, ces nouveaux indicateurs permettraient une double traçabilité : d'une part l'amélioration du calcul de dose puis l'efficacité du traitement ; d´ autre part, la sécurité du traitement et de la technique utilisée. / In external radiation therapy, the treatment is delivered to the patient with a fraction every day using the treatment established before and repeated until the end of the treatment. Treatment planning is establish using anatomical information of the patient and a dose calculation. New technologies already integrated to the treatment units can be used to check the positioning of the patient and anatomical information (Electronic Portal Imaging Device - EPID-, Cone Beam Computed Tomography - CBCT - ).The main goal is to develop a system to control the dose delivered to the patient from the dose establish with the TPS.The first aim of this work is to integrate portal images to compare and assess the position of the patient at each fraction to the planned one (CT images) by accepting, rejecting or ignoring the patient positioning and dose level discrepancy according to a tolerance threshold defined by the user. The second aim is to integrate on boardimaging to reconstruct the delivered dose using a dose calculation. Following the dose received by the patient day after day, based on new indicators, it can be established a traceability to identify deviation and assess treatment quality.To conclude, these new indicators would allow a double traceability : in one hand the improvement of the calculation and then the efficiency of the treatment ; in another hand the safety of the treatment and the technique used.

Background: Primary CNS Lymphoma is a rare and severe but potentially curable disease. In the last thirty years treatment has changed significantly. Survival times increased due to high-dose methotrexate-based chemotherapy. With intensive regimens involving autologous stem cell transplantation (ASCT), 4-year survival rates of more than 80% can be reached. However, this treatment regimen is not feasible in all patients, and is associated with some mortality. Methods: In this review, current evidence regarding the efficacy and toxicity of radiotherapy in PCNSL shall be summarized and discussed mainly based on data of controlled trials. Results: Being the first feasible treatment whole brain radiotherapy (WBRT) was initially used alone, and later as a consolidating treatment after high-dose methotrexate-based chemotherapy. More recently, concerns regarding activity and neurotoxicity of standard dose WBRT limited its use. On the contrary, latest evidence of some phase II trials suggests efficacy of consolidating WBRT is comparable to ASCT. After complete remission reduced dose WBRT appears as a feasible concept with decreased neurotoxicity. Evidence for use of local stereotactic radiotherapy is very limited. Conclusion: Radiotherapy has a role in the treatment of PCNSL patients not suitable to ASCT, e.g., as consolidating reduced dose WBRT after complete response. Local stereotactic radiotherapy for residual disease should be examined in future trials.

<p>Studija je imala za cilj da pokaže značaj primene PET/CT pregleda u planiranju radiolo&scaron;ke terapije kod pacijenata obolelih od Hočkinovog linfoma. U Vojvodini je 2009. godine prema podacima Registra za maligne neoplazme Vojvodine incidence za Hočkinov limfom iznosila 2,7 na 100 000 dok je mortalitet bio 1,1 na 100 000 stanovnika. Na osnovu dostupnih podataka Registra za maligne neoplazme Vojvodine beleži se porast incidence u protekloj deceniji. Procenat obolelih u Vojvodini u korelaciji je sa podacima koje navodi i Međunarodna agencija za istraživanje raka iz Liona (IARC). U Evropi i u Sjedinjenim Američkim Državama postoji bimodularna kriva incidence po starosti koja pokazuje maksimalne vrednosti u period između 20 i 30 godina i nakon 55. godine. S obzirom da od Hočkinovog limfoma dominantnije obolevaju mlađe osobe a da bolest ima dobru prognozu neophodno je iznaći nove načine za inicijalno određivanje stadijuma bolesti, kao i metode koje mogu da unaprede kvalitet lečenja. Jedan od načina je primena &scaron;to savremenijih dijagnostičkih metoda. PET-CT je imidžing metoda koja poslednjih godina zauzima značajno mesto u određivanju stadijuma malignih bolesti kao i u proceni odgovora na primenjenu terapiju. Fuzionisanjem skenova PET-a i CT-a dobija se PET-CT slika koja prikazuje funkcionalno stanje pojedinih tkiva i organa (PET) sa anatomskim detaljima (CT). Cilj istraživanja je bio da se utvrdi prednost PET-CT pregleda u planiranju radioterapije kod pacijenata sa supradijafragmalnom lokalizacijom bolesti. Nakon postavljanja dijagnoze Hočkinovog limfoma kod pacijenata je urađen PET-CT i planiranje radiolo&scaron;ke terapije. Zračna terapija je planirana na osnovu nalaza PET-CT-a i njegovom fuzijom sa CT-om za planiranje radiolo&scaron;kog lečenja. Dobijeni planovi su poređeni sa onim koji su rađeni standardnom 3D konformalnom tehnikom bez fuzije. Poređeni su klinički volumeni (CTV) i planirani volumen (PTV) kao i razlike u njihovoj obuhvaćenosti preskribovanom dozom. Pokazano je da postoji statistički značajna razlika u ciljnim volumenima kao i u njihovoj obuhvaćenosti. Posmatrani su takođe i rizični organi- srce, pluća, dojke, &scaron;titasta žlezda, kičmena moždina i doze koje oni prime. Dokazano je da su sa statističkom značajno&scaron;ću dozna opterećenja na navedene rizične organe manja kada se planiranje vr&scaron;i na osnovu fuzije sa PET-CT-om, te se na osnovu toga može reći da će i očekivane manifestacije kasne toksičnosti biti manje. Istraživanjem je potvrđena hipoteza da PET/CT ima veliku prednost u planiranju radioterapije jer smanjuje zapremine ciljnih volumena i doprinosi pobolj&scaron;anju kvaliteta radiolo&scaron;kog lečenja.</p> / <p>This study aimed to prove that the use of PET/CT in radiotherapy planning makes a material change in the course of the treatment of the patients with Hodgkin&#39;s lymphoma. According to the data from the Registry of malignant neoplasms in Vojvodina, incidence of Hodgkin&#39;s lymphoma in Vojvodina in 2009 was 2.7 per 100 000, while the mortality rate was 1.1 per 100 000 inhabitants. Based on the available data, the said Register recorded an increase in the incidence over the past decade. The percentage of patients who were registered in Vojvodina is in correlation with the data cited by the International Agency for Research on Cancer in Lyon (IARC).In Europe and in the United States the disease has a bi-modular distribution distribution with the highest frequency rate in persons ageing from 20-30 years and people older than 55 years. Due to the fact that the dominant Hodgkin&#39;s lymphoma affects young people and having in mind the good prognosis of the disease, it is necessary to find a new modality for the initial staging of disease and methods which can improve the quality of treatment. PET/CT is the imaging method which has in recent years had an important role in the staging of malignancies, as well in the evaluation of response to therapy. PET/CT image is obtained by fusing PET scans with CT and it show functional status of certain tissues and organs (PET) with anatomical details (CT).The object of this study was to show that PET/CT examinations are preferred imaging method in radiotherapy planning in patients with localized disease above the diaphragm. After they had been diagnosed with HL, patients underwent PET/CT scan which was later used for delineation in radiotherapy planning. In this study, radiation therapy was planned on the basis of the findings of PET /CT and its fusion with CT for planning radiological treatment. The resulting plans were compared with those made using standard 3D conformal technique without fusion. Clinical volume (CTV) and the planned volume (PTV) and the differences in their coverage with the prescription dose in both plans were also compared. The study has shown a statistically significant difference in the target volume and their coverage. In addition, the dose which receive organs at risk was also examined. It has been shown that organs at risk were exposed to lower doses when using PET/CT fusion in radiotherapy planning and consequently, less incidence of late toxicity is to be expected. The study confirmed the hypothesis that PET /CT has a great advantage in the planning of radiotherapy because it reduces the volume of the target volume and improves the quality of radiation treatment.</p>

As técnicas de radioterapia vem sendo constantemente modificadas com a implementação de novas tecnologias visando aumentar a eficiência e diminuir a toxicidade dos tratamentos com radiação ionizante. Esse trabalho visa comparar as técnicas de radioterapia de intensidade modulada (IMRT) e a radioterapia em arco modulada volumetricamente (VMAT) em termos dosimétricos para o alvo e órgãos em risco além de avaliar a diferença do tempo de tratamento utilizando cada técnica. Para assegurar que os planejamentos seguiriam um padrão aceitável para ambas as técnicas, realizou-se primeiramente os planejamentos sugeridos pelo TG 119 da Associação Americana de Física Médica e compatibilidade dos resultados obtidos comparados com os dados da literatura. Tal comparação permitiu prosseguir para uma próxima etapa que consistiu da utilização de imagens de pacientes reais que foram submetidos a tratamentos de próstata e cabeça e pescoço, para a realização dos planejamentos utilizando as técnicas de IMRT e VMAT. A qualidade dosimétrica dos planejamentos utilizando ambas as técnicas foi avaliada em termos de conformidade e homogeneidade da dose no alvo e para os casos de pacientes com câncer de próstata, foram investigados os limites de dose em reto, bexiga e cabeça de fêmur, sendo avaliada a associação entre o volume de intersecção de reto e bexiga com o alvo. Para os   casos de pacientes com câncer de cabeça e pescoço, em termos dos limites de dose em medula, tronco cerebral e parótidas. Os planejamentos nos quais fez se uso da técnica de VMAT apresentaram valores semelhantes aos dos planos de IMRT. A análise dos tempos de tratamento para cada técnica avaliada mostrou que a VMAT reduz significativamente o tempo, até 67% para os casos de pacientes com câncer de próstata e até 36% para os casos de pacientes com câncer de cabeça e pescoço / The goal of this study was to compare the dosimetric aspects of volumetric-modulated arc therapy (VMAT) with those of intensity-modulated radiotherapy (IMRT) and to evaluate the delivery time and monitor unit differences between the two techniques, for applications in prostate and head and neck cancer treatment. First of all, to assure an acceptable pattern of treatment planning using both techniques, the TG119 of American Association of Medical Physics instructions were followed and the results of plans were compared to TG119 published data. The next step consisted of using real patients\' images, whose underwent prostate radiotherapy or head and neck radiotherapy, to planning IMRT and VMAT. The dosimetric quality of plans using both techniques was evaluated in terms of target dose conformity and target dose homogeneity The dose constraints for rectum, bladder and femoral head were analyzed and the association between the rectum intersection volume and bladder intersection volume to the target volume were evaluated for the prostate cases. The dose constraints for spinal cord, brainstem and parotids were investigated for the head and neck cases. Best or similar values were obtained for the VMAT plans in relation to IMRT plans. The analysis of treatment time indicated a significant reduction using VMAT, until 67% to the prostate cases and 36% to the head and neck cases