Durante ou após o tratamento, quimio ou radioterápico, o cirurgião-dentista deve atuar na prevenção e no tratamento das sequelas e lesões bucais que possam ocorrer. A laserterapia possui um papel fundamental e inovador considerando-se algumas repercussões bucais decorrentes da radioterapia (RT) e da quimioterapia (QT) especialmente quanto a mucosite bucal e a xerostomia. Foi realizado um levantamento dos prontuários de pacientes sob tratamento de neoplasias na região da cabeça e pescoço que foram submetidos à laserterapia de baixa potência no Laboratório Especial de Laser em Odontologia (LELO) da FOUSP, com objetivo de verificar a adequação e efetividade do protocolo terapêutico, estabelecido para os pacientes na prevenção e no tratamento da mucosite oral pós radio e/ou quimioterapia. Examinados cem prontuários de pacientes submetidos a protocolo de laserterapia de baixa potência (LBP) diodo InGaAlP com 660 nm, 40 mW, 6 J/cm2 em um tempo de 6 segundos por ponto em 49 pontos para o tratamento e/ou prevenção das principais manifestações bucais relacionadas a RT (concomitante ou não com cirurgia e/ou QT), atendidos no período de 2007 a 2010. Não foram incluídos os prontuários que não descreviam a periodicidade das aplicações para prevenção e/ou tratamento com LBP, a evolução clínica do paciente frente à laserterapia, dados daqueles pacientes que estavam em tratamento e relacionados a neoplasias outras que não na região de cabeça e pescoço. Foram incluídos na análise os seguintes dados para o levantamento: gênero do paciente, idade, hábitos nocivos (tabagismo, etilismo), frequência e hábitos de higiene bucal, diagnóstico e região da neoplasia, estadiamento TNM, dose total da RT recebida, outros tratamentos relacionados (cirurgia e/ou quimioterapia), queixa principal odontológica/estomatológica. O diagnóstico da mucosite seguiu os Critérios de Toxicidade Comum do Instituto Nacional de Câncer para escala de mucosite oral radio-induzida. Foram colhidos dados quanto ao protocolo de laserterapia de baixa potência utilizados para os casos de mucosite quanto ao período do tratamento, número total de sessões de laserterapia, a frequência das aplicações e desfecho clínico: expresso pelo paciente e/ou avaliação pelo clínico assistente. Os dados obtidos foram apresentados de forma descritiva, em percentuais e médias. Foram selecionados sessenta e três prontuários referentes a neoplasias na região da cabeça e pescoço. O total de prontuários válidos foi dividido em dois grupos: prevenção (n=21) e tratamento (n=42). No grupo de prevenção foram considerados aqueles relativos às aplicações antes da primeira manifestação da mucosite oral. No grupo tratamento consideraram-se aqueles com descrição de aplicações de laser em lesões de mucosite oral. O protocolo utilizado foi capaz de reduzir as lesões e diminuir as manifestações clínicas da mucosite oral em todos os pacientes tratados. A extensão do tempo de tratamento está na dependência de fatores locais como a presença de infecção, nível de higiene bucal bem como a de fatores sistêmicos como o estado nutricional, os hábitos nocivos como tabagismo e etilismo e outras comorbidades como o diabetes. / During or after chemo or radiotherapy, the dentist should play an important role in the prevention and treatment of oral lesions and sequelae that can occur. Laser therapy has some innovative impact especially for therapeutic of oral mucositis and xerostomia. We conducted a survey of archives, of patients after treatment of malignancies in the head and neck who underwent low level laser therapy in the Special Laboratory of Laser in Dentistry (LELO) at Dental School of University of São Paulo in order to verify the suitability of therapeutic protocol for patients in the prevention and treatment of oral mucositis after radiotherapy. One hundred registers of patients undergoing protocol of low level laser (LLL) InGaAlP diode with 660 nm, 40 mW, 6 J/cm2 at a time 6 seconds per point at 49 points for the treatment or prevention of oral mucositis manifestations related to RT (concomitant or not with surgery and/or QT). Records that did not describe timing of applications of LLL for prevention and/or treatment and lack of clinical course of the patient toward lasertherapy were not included on the evaluation. The analysis included: patient gender, age, smoking habits, alcohol use, frequency and oral hygiene practice, diagnosis and region of the tumor, TNM stage, total dose of RT received, other related treatments: surgery and chemotherapy, the primary oral complaint. Diagnosis of mucositis followed the Common Toxicity Criteria of the National Cancer Institute for the level of oral mucositis radio induced. It was collected data from the protocol of low level laser therapy used in cases of mucositis the period of the total number of treatment sessions laser therapy, the frequency of applications, clinical outcome, expressed by the patient and / or evaluation by the clinical assistant. The data were presented descriptively in percentages and averages. We selected sixty-three records relating to neoplasms in the head and neck. The total number of valid records was divided into two groups: prevention (n= 21) and treatment (n= 42). In the prevention group it was considered those related to applications before the first manifestation of oral mucositis. In the treatment group it was considered those with a description of laser applications in presented oral mucositis lesions. The protocol used was able to reduce injuries and lessen the clinical manifestations of oral mucositis in all patients treated. Treatments time length was dependent on local factors such as presence of infection, level of oral hygiene as well as systemic factors such as nutritional status, harmful habits like smoking and alcoholism and other disease as diabetes.

O processo de radioterapia consiste em várias etapas, iniciando na indicação pelo médico. O plano de tratamento passa então por um processo denominado simulação, onde é adquirida uma série de imagens por tomografia computadorizada que são transferidas para o sistema de planejamento, onde a delineação dos volumes alvos e tecidos normais adjacentes serão realizadas. Após a delineação desses volumes, no sistema de planejamento são colocados os campos de irradiação e a dose desejada conforme prescrição médica. O sistema de planejamento calcula então a dose que o volume alvo e os tecidos adjacentes poderão receber. Se estas doses estão dentro dos padrões aceitáveis, o planejamento então é aprovado e enviado ao acelerador linear para a execução do tratamento. Antes da execução do tratamento, é realizada uma imagem, seja através de filme radiográfico ou digitalmente, para avaliar a posição no paciente na mesa de tratamento. Se a localização do paciente está correta, a dose é então liberada. Esse protocolo de aquisição de imagem é denominado como Radioterapia Guiada por Imagem (IGRT). A quantidade de radiografias de posicionamento segue um protocolo definido conforme a região a ser irradiada. Como resultado deste procedimento, sabe-se que uma determinada dose adicional é recebida pelos pacientes, tornando-se um fator importante a ser determinado. Esta avaliação foi realizada através da simulação de Monte Carlo, utilizando o código MCNP. Para isso foi realizada primeiramente toda a caracterização da fonte de raios X com uso de câmaras de ionização e dosimetros TL juntamente com as simulações no MCNP. Após essa caracterização, as imagens e as estruturas do planejamento radioterápico foram convertidas para serem utilizadas no código MCNP. Para que as doses fossem calculadas nos principais órgãos de risco no tratamento de próstata: bexiga, reto e cabeças de fêmur direita e esquerda. / The process of radiotherapy treatment consists of several stages, starting from the statement given by the physician. The treatment planning undergoes a process called simulation, where a series of computed tomography images is acquired and transferred to the treatment planning system, where the delineation of target volumes and adjacent normal tissues will be performed. After the delineation of these volumes, then irradiation fields and dose precribed by the physician are placed in the treatment planning system. It calculates the dose that target volume and surrounding tissues are receiving. If the doses are within acceptable standard values, then the design is approved and submitted to the linear accelerator for the treatment course. Before treatment course, an image is performed, either by radiographic or digital film, in order to evaluate (check) the patient position on the treatment table. If the patient position is correct, the treatment is realized. This image acquisition protocol is called Image-Guided Radiotherapy (IGRT). The amount of radiographic positioning follow a protocol defined for the region to be treated. As a result of this procedure, it is known that a specific additional dose is received by the patient, becoming an important factor to be determined. In this work, this additional dose evaluation was performed by the Monte Carlo simulation using the MCNP algorithm. The characterization of the entire X-ray source was primarily realized with ionization chamber thermoluminescent dosimeters and simulations with the MCNP code. After the X-ray tube characterization, images and the structures for the radiotherapy planning were converted to be used in the MCNP code for dose calculation at the main organs at risk during a prostate treatment: bladder, rectum and femoral heads right and left.

O tratamento dos gliomas malignos cerebrais é um dos grandes desafios da medicina atualmente, pois, apesar do grande avanço no conhecimento destes tumores, o prognóstico de vida dos portadores desta doença é muito ruim. Foram estudados retrospectivamente 61 pacientes com diagnóstico de glioblastoma multiforme ou astrocitoma anaplásico, no período de 1998 a 2002, com o objetivo de avaliar o uso do Paclitaxel como potencializador do tratamento radioterápico destes tumores. Todos os pacientes foram tratados inicialmente com cirurgia para retirada ampla do volume tumoral (mínimo de 80%) seguido de tratamento com radioterapia fracionada e reforço com radiocirurgia estereotáxica. Em caso de crescimento tumoral, após o tratamento inicial dos pacientes com KPS > 70, novo tratamento cirúrgico e nova radiocirurgia foram indicados. Destes 61 pacientes, 32 receberam tratamento com Paclitaxel, na dose de 100mg/m2 e 29 pacientes não receberam nenhum tipo de quimioterápico. Os grupos foram comparados, em relação ao tipo histológico, faixa etária, sexo e localização tumoral, não havendo diferenças estatisticamente significantes entre os mesmos. Os pacientes de ambos os grupos tiveram acompanhamento laboratorial antes, durante e após o tratamento com paclitaxel e foram acompanhados até o óbito causado pela doença. Foram excluídos do estudo os portadores de tumor que foram a óbito por outras causas. A análise dos resultados mostrou que não houve diferenças estatísticas em relação à sobrevida média do grupo tratado com Paclitaxel e o grupo sem o tratamento (p=1,000). Da mesma forma, a comparação entre os pacientes com glioblastomas (p=0,8933) e com astrocitomas anaplásicos (p=0,5920) de ambos os grupos não mostrou diferença estatística em relação à sobrevida. O número de craniotomias( p=0,5268) e o número de radiocirurgias (p=0,3666) foram semelhantes estatisticamente. Os estudos laboratoriais realizados durante o tratamento no grupo que recebeu o paclitaxel, não mostraram alterações que levassem à suspensão do tratamento. A análise dos resultados deste estudo permitiu concluir que o uso do paclitaxel, concomitante ao tratamento radioterápico dos gliomas malignos cerebrais, não mostrou nenhum ganho adicional na sobrevida dos pacientes portadores destes tumores e, pela análise da necessidade de novo tratamento durante o curso da doença, não potencializou os efeitos da radioterapia. Palavras-chave: Paclitaxel, gliomas malignos, radioterapia / Nowadays, the treatment of the malignant cerebral gliomas is one of the greatest challenges for neurosurgons. Despite of the advance regarding these tumors? knowledge expectance of life for these patients is very bad. The main purpose of this study was to evaluate the use of paclitaxel to enhance the radiotherapy treatment in those tumors. Sixty-one patients with diagnosis for glioblastoma multiforme or anaplastic astrocytoma in the period of 1998 to 2002 were, retrospectively, studied. All patients were initially treated with surgery in order to remove a wide portion of the tumor?s volume (minimum of 80%). Then, the patients were treated with fractionated radiotherapy and reinforcement with stereotactic radiosurgery. If there was an increase in the tumor after the initial treatment, the patients with a KPS higher than 70 had new treatment with surgery as well as with radiosurgery. Among the 61 patients, 32 were treated with a 100 mg/m2 dose of paclitaxel, and 29 of then did not have any kind of chemotherapy treatment. Comparisons bettwen both regardhg to the histological type, age, gender and location of the tumor showed no differences . Patients of both groups had a laboratory follow-up before, during and after the treatment with paclitaxel. All of them were followed until their death, which was caused by the disease. Patients that died from other diseases were not included in the study. The analysis of the results indicated that there were no statistics differences regarding the mean survival time between the groups treated or nor treated with paclitaxel ( p=1,000). Likewise, a comparison between the glioblastomas (p=0,8933) and the anaplastic astrocytomas (p=0,5920) of both groups did not indicate any statistic difference regarding to the survival time. The was no statistic difference between the number of craniotomies (p=0,5268) as well as between the number of radiosurgeries. (p=0,3666). The laboratory studies held during the treatment of the group that received the paclitaxel did not show any changes which could lead to cease the treatment. Hence the results led to the conclusion that the treatment of malignant cerebral gliomas with paclitaxel and radiotherapy treatment at the same time did not give any additional gain in the patients?survival. Regarding to the demand for new treatment throughout the disease, there was no enhance of the radiotherapy effects with the Paclitaxel. Key words: Paclitaxel, malignant gliomas, radiotherapy.

Orientador: Marinês Nobre dos Santos Uchôa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-24T17:54:51Z (GMT). No. of bitstreams: 1 Lopes_LenitaMarangoni_M.pdf: 1281003 bytes, checksum: d8db3df30e9d6a94643ef468e60b5af8 (MD5) Previous issue date: 2014 / Resumo: A saliva é um importante fator de proteção contra doenças bucais devido a propriedades como clearence promovido pelo fluxo salivar e manutenção do pH em níveis aceitáveis pela capacidade tampão. Entretanto, inúmeros fatores podem afetar a produção de saliva, podendo resultar em hipossalivação e no sintoma de boca seca, a xerostomia. Estudos mostram que uma das causas da hipossalivação é a radioterapia envolvendo a região de cabeça e pescoço, utilizada no tratamento de câncer. Dentre as neoplasias em crianças que incluem em seus protocolos de tratamento a radioterapia na região cervical, destacamos o Linfoma de Hodgkin, o qual frequentemente acomete cadeias ganglionares cervicais. Sendo assim, o primeiro objetivo do presente estudo foi investigar se a radioterapia causa algum efeito sobre o fluxo, o pH e a capacidade tampão da saliva de crianças com Linfoma de Hodgkin. O segundo objetivo foi avaliar se existe correlação entre as características salivares descritas acima e parâmetros que exprimem a qualidade de vida antes, durante e após o tratamento radioterápico. Para tanto, foi realizada a coleta de saliva estimulada e não estimulada e aplicação do questionário H&N35 a 10 voluntários de 6 a 16 anos, portadores de Linfoma de Hodgkin, antes do início do tratamento (baseline), ao completarem as doses de 1000 e 2000 cGy, e após 1, 2 e 3 meses do final da radioterapia. Como grupo controle, 10 voluntários saudáveis pareados por idade e sexo foram submetidos à única coleta de saliva. O volume de saliva coletada foi dividido pelo tempo de coleta para estimar do fluxo salivar. A saliva coletada foi utilizada para avaliação do pH e da capacidade tampão pelo método da titulação. O questionário foi interpretado de acordo com as recomendações da European Organization for Research and Treatment of Cancer (EORTC). Os resultados do estudo mostraram que em relação ao controle, o fluxo salivar estimulado foi significativamente menor no início do estudo (baseline), bem como após as doses de 1000, 2000 cGy e 1, 2 e 3 meses após o tratamento. Ainda, o fluxo salivar estimulado observado após a dose de 1000 cGy e 1 mês após o tratamento foi significativamente inferior aquele do baseline. O pH da saliva não estimulada diminuiu após 3 meses em relação ao grupo controle, mas não houve diferença entre o pH salivar no baseline e qualquer outro grupo. O pH da saliva estimulada foi menor após 1 e 3 meses, quando comparado ao grupo controle. A capacidade tampão da saliva não estimulada e estimulada foi reduzida após a dose de 2000 cGy. Os voluntários relataram uma maior intensidade de boca seca e dor após as doses de 1000 e 2000 cGy. Além disso, para saliva não estimulada, exceto entre pH e dor após a dose de 2000 cGy, uma correlação significativa foi encontrada entre dor, boca seca e todas as variáveis investigadas em todas as fases. Para saliva estimulada não foi observada correlação apenas entre o pH e a dor após a dose de 2000 cGy e 2 meses após o tratamento. Então, pode-se concluir que o protocolo radioterápico, ao qual os voluntários foram submetidos, produziu alterações na taxa de fluxo salivar e capacidade tampão da saliva; e estas alterações tiveram impacto negativo na qualidade de vida, em relação à intensidade de boca seca e sensação de dor na cavidade bucal da crianças avaliadas / Abstract: Saliva is an important protective factor for oral diseases due to properties such as clearance by salivary flow, and maintenance of pH within acceptable levels by buffer capacity. However, many factors can affect saliva production, which can result in hypossalivation and symptoms of dry mouth, the xerostomia. Studies have shown that one of the causes of hypossalivation is radiotherapy of head and neck used to treat cancer. Among children's neoplasms that include in their treatment protocols the radiotherapy of cervical region, we highlight the Hodgkin's lymphoma, which often affects cervical ganglion. Thus, the first aim of this study was to investigate if the radiotherapy treatment has any effect on the salivary flow rate, pH and buffering capacity of stimulated and unstimulated saliva of children with Hodgkin's lymphoma. The second aim of our study was to evaluate if there is any correlation between these salivary parameters and some areas that express the quality of life before, during and after radiotherapy treatment. To do so, stimulated and unstimulated saliva was collected and the H&N35 questionnaire was applied to 10 children and adolescents aging 6-16 years old, with Hodgkin's lymphoma before the start of treatment (baseline), after the 1000 and 2000 cGy doses were completed, and after 1, 2 and 3 months of the end of the radiotherapy. As a control group, a single saliva collection was performed in 10 healthy children of the same age group. The volume of saliva collected was divided by the time of collection to estimate the salivary flow rate. The collected saliva was used to evaluate the pH and the buffer capacity by the titration method. The questionnaire was interpreted according to recommendations of the European Organization for Research and Treatment of Cancer (EORTC). The results of the study showed that when compared to control group, an decrease unstimulated salivary flow rate was found after the dose of 1000 cGy and after 1 month but no difference among groups was found. Stimulated salivary flow rate was significantly lower at baseline as well as after the doses of 1000, 2000 cGy and 1, 2 and 3 months after treatment when compared to control group. In the same way, a significantly lower stimulated salivary flow rate was observed after the dose of 1000 cGy and 1 month after treatment when compared to baseline. The pH of unstimulated saliva decreased after 3 months as compared to control group but no difference was found among salivary pH at baseline and any other group. The pH of stimulated saliva was lower after 1 and 3 months when compared to control group. The buffering capacity of unstimulated and stimulated saliva was reduced after the dose of 2000 cGy. The volunteers reported a greater intensity of dry mouth and pain after doses of 1000 and 2000 cGy. Moreover, for unstimulated saliva, except for the absence of correlation between pH and pain after the dose of 2000 cGy, a significant correlation was found among pain, dry mouth and all investigated variables in all phases. For stimulated saliva no correlation between pH and pain after the dose of 2000 cGy and 2 months after treatment could be detected. Then, it can be concluded that the radiotherapic protocol, to which the volunteers were submitted, produced changes in salivary flow rate and buffering capacity of saliva and that these changes negatively impacted the quality of life regarding the intensity of dry mouth and pain sensation in the oral cavity of evaluated children / Mestrado / Odontopediatria / Mestra em Odontologia

Radiation therapy has been shown to increase local and regional control as well as overall survival with breast cancer, but the vast majority of patients develop acute skin reactions, which are in part related to microvascular changes. These reactions vary between different skin sites. The aim of this work is to determine the absorbed dose to the skin by measurements and investigate if there is a correlation between the absorbed dose at different areas of the breast and the local changes in microcirculation in the skin after breast cancer radiotherapy. The study includes characterisation of the Gafchromic EBT3 film and Epson Perfection V600 Photo scanner which are used for absorbed dose determination. The measurements were done both on an anthropomorphic female phantom and on a patient undergoing breast cancer radiotherapy. Twenty-one pieces offilm (2x1 cm2) were placed on the surface of the breast (both for the phantom and patient) and irradiated with a prescribed dose to the target of 2.66 Gy with two opposed fields using 6 MV beam. It was observed that mainly 45-64 % of the prescribed dose was deposited at the surface, both for the phantom and patient. Using laser speckle contrast imaging and polarised light spectroscopy, the regional changes in mean blood perfusion and in mean red blood cell concentration (RBCC) at the end of the treatment with a total prescribed dose of 42.6 Gy, compared to baseline, were measured in both the treated and untreated breast of the same patient. Although marked increases in perfusion were seen in different areas of the treated breast, there was no significant correlation between the changes in perfusion and the absorbed dose at these areas. However, a statistical correlation was found between the changes in RBCC and the absorbed skin dose at the same areas. To further elucidate the relation between the changes in skin microcirculation and the absorbed radiation dose during breast cancer radiotherapy, future studies using a larger number of patients are needed.

Le cancer de la prostate est le cancer le plus fréquent chez les hommes dans la plupart des pays développés. C'est le cancer le plus fréquent chez les hommes en France (73.609 cas en 2014) et en Colombie (9564 cas en 2014). En outre, c'est la troisième cause de décès par cancer chez les hommes dans les deux pays (9,3 % en France et 7,1 % en Colombie en 2014). L'une des techniques de traitement est la radiothérapie externe, qui consiste à délivrer un rayonnement ionisant à une cible clinique, à savoir la prostate et les vésicules séminales. En raison des variations anatomiques au cours du traitement, qui consiste en environ 40 fractions de rayonnement délivrant une dose totale allant de 70 à 80Gy, des marges de sécurité sont définies autour de la cible tumorale lors de la planification du traitement. Ceci entraîne des portions d'organes sains voisins de la prostate - la vessie et le rectum - à être inclus dans le volume cible, pouvant conduire à des événements indésirables affectant les fonctions urinaires (hématurie et cystite, entre autres) ou rectale (saignement rectal, incontinence fécale, Etc.). La vessie présente les plus grandes variations de forme entre fractions de traitement, provoquées par des changements continus de volume. Ces variations de forme introduisent des incertitudes géométriques qui rendent difficile l'évaluation de la dose réellement délivrée à la vessie pendant le traitement. Ces incertitudes limitent la possibilité de modéliser une relation dose-volume pour la toxicité génito-urinaire tardive (GU). Le projet QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) a déclaré que la relation dose-réponse pour la toxicité gastro-intestinale tardive (GI) était loin d'être établie. Les variables dosimétriques obtenues à partir de la tomodensitométrie de planification peuvent être faiblement représentative de la dose effectivement administrée. En conséquence, il est crucial de quantifier les incertitudes produites par les variations inter-fraction de la vessie afin de déterminer les facteurs dosimétriques qui affectent les complications GU tardives. Le but de cette thèse était donc de caractériser et de prédire les incertitudes produites par les variations géométriques de la vessie entre les fractions de traitement, en utilisant uniquement la tomodensitométrie de planification comme information d'entrée. En pratique clinique, une seule tomodensitométrie est disponible au moment de la planification du traitement pour un patient typique, alors que des images supplémentaires peuvent être acquises en cours de traitement. Dans cette thèse une approche population a été utilisée pour obtenir suffisamment de données pour apprendre les directions les plus importantes du mouvement et de la déformation de la vessie en utilisant l'analyse en composante principales (ACP). Comme dans les travaux de référence, ces directions ont ensuite été utilisées pour développer des modèles basés population pour prédire et quantifier les incertitudes géométriques de la vessie. Cependant, nous avons utilisé une analyse longitudinale afin de caractériser correctement la variance du patient et les modes spécifiques du patient à partir de la population. Nous avons proposé d'utiliser un modèle à effets mixtes (ME) et une ACP hiérarchique pour séparer la variabilité intra et inter-patients afin de contrôler les effets de cohorte confondus. Finalement, nous avons présenté des modèles sur l'APC comme un outil pour quantifier des incertitudes de la dose produit par le mouvement et déformation de la vessie entre fractions. / Prostate cancer is the most common cancer amongst the male population in most developed countries. It is the most common cancer amongst the male population in France (73.609 cases in 2014) and in Colombia (9564 cases in 2014). It is also the third most common cause of cancer deaths in males in both countries (9.3% and 7.1% in France and in Colombia in 2014, respectively). One of the standard treatment methods is external radiotherapy, which involves delivering ionizing radiation to a clinical target, namely the prostate and seminal vesicles. Due to the uncertain location of organs during treatment, which involves around forty (40) radiation fractions delivering a total dose ranging from 70 to 80Gy, safety margins are defined around the tumor target upon treatment planning. This leads to portions of healthy organs neighboring the prostate or organs at risk — the bladder and rectum — to be included in the target volume, potentially resulting in adverse events affecting patients’ urinary (hematuria and cystitis, among others) or rectal (rectal bleeding, fecal incontinence, etc.) functions. The bladder is notorious for presenting the largest inter-fraction shape variations during treatment, caused by continuous changes in volume. These variations in shape introduce geometric uncertainties that render assessment of the actual dose delivered to the bladder during treatment difficult, thereby leading to dose uncertainties that limit the possibility of modeling dose-volume response for late genitourinary (GU) toxicity. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) project has stated that a similar dose-response to that of late gastrointestinal (GI) toxicity is far from being established. The dosimetric variables obtained from the planning CT prove to be very poor surrogates for the real delivered dose. As a result, it appears crucial to quantify uncertainties produced by inter-fraction bladder variations in order to determine dosimetric factors that affect late GU complications. The aim of this thesis was thus to characterize and predict uncertainties produced by geometric variations of the bladder between fractions, using solely the planning CT as input information. In clinical practice, a single CT scan is only available for a typical patient during the treatment planning while on-treatment CTs/CBCTs are seldom available. In this thesis, we thereby used a population approach to obtain enough data to learn the most important directions of bladder motion and deformation using principal components analysis (PCA). As in groundwork, these directions were then used to develop population-based models in order to predict and quantify geometrical uncertainties of the bladder. However, we use a longitudinal analysis in order to properly characterize both patient-specific variance and modes from the population. We proposed to use mixed-effects (ME) models and hierarchical PCA to separate intra and inter-patient variability to control confounding cohort effects. . Subsequently, we presented PCA models as a tool to quantify dose uncertainties produced by bladder motion and deformation between fractions.

The search for the optimal choice of treatment time, dose and fractionation regimen is one of the major challenges in radiation therapy. Several aspects of the radiation response of tumours and normal tissues give different indications of how the parameters defining a fractionation schedule should be altered relative to each other which often results in contradictory conclusions. For example, the increased sensitivity to fractionation in late-reacting as opposed to early-reacting tissues indicates that a large number of fractions is beneficial, while the issue of accelerated repopulation of tumour cells starting at about three weeks into a radiotherapy treatment would suggest as short overall treatment time as possible. Another tumour-to-normal tissue differential relevant to the sensitivity as well as the fractionation and overall treatment time is the issue of tumour hypoxia and reoxygenation. The tumour oxygenation is one of the most influential factors impacting on the outcome of many types of treatment modalities. Hypoxic cells are up to three times as resistant to radiation as well-oxygenated cells, presenting a significant obstacle to overcome in radiotherapy as solid tumours often contain hypoxic areas as a result of their poorly functioning vasculature. Furthermore, the oxygenation is highly dynamic, with changes being observed both from fraction to  fraction and over a time period of weeks as a result of fast and slow reoxygenation of acute and chronic hypoxia. With an increasing number of patients treated with hypofractionated stereotactic body radiotherapy (SBRT), the clinical implications of a substantially reduced number of fractions and hence also treatment time thus have to be evaluated with respect to the oxygenation status of the tumour. One of the most promising tools available for the type of study aiming at determining the optimal radiotherapy approach with respect to fractionation is radiobiological modelling. With clinically validated in vitro-derived tissue-specific radiobiological parameters and well-established survival models, in silico modelling offers a wide range of opportunities to test various hypotheses with respect to time, dose, fractionation and details of the tumour microenvironment. Any type of radiobiological modelling study intended to provide a realistic representation of a clinical tumour should therefore take into account details of both the spatial and temporal tumour oxygenation. This thesis presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various fractionation schemes, and oxygenation levels and dynamics using different survival models. The results of this work indicate that hypoxia and its dynamics play a major role in the outcome of radiotherapy, and that neglecting the oxygenation status of tumours treated with e.g. SBRT may compromise the treatment outcome substantially. Furthermore, the possibilities offered by incorporating modelling into the clinical routine are explored and demonstrated by the development of a new calibration function for converting the uptake of the hypoxia-PET tracer 18F-HX4 to oxygen partial pressure, and applying it for calculations of the doses needed to overcome hypoxia-induced radiation resistance. By hence demonstrating how the clinical impact of hypoxia on dose prescription and the choice of fractionation schedule can be investigated, this project will hopefully advance the evolution towards routinely incorporating functional imaging of hypoxia into treatment planning. This is ultimately expected to result in increased levels of local control with more patients being cured from their cancer. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 6: Manuscript.</p>

It is well established that many solid tumours are heterogeneous with respect to oxygenation, and contain regions of hypoxic cells, which due to their inherent resistance to ionizing radiation, limit the success of radiotherapy. Numerous chemicals and drugs have been investigated over the past few decades as potential radiosensitizers. The most notable of these being the organometallic compound, cis-diammine dichloroplatinum(II). The clinical success of this drug led to the synthesis of other types of organic cytotoxic metal-containing drugs. Prof. J.C. Swart from the University of the Orange Free State supplied seventeen novel iridium, ferrecenium and rhodium complexes, which I screened for cytotoxic activity against the CHO cell line. The two most cytotoxic complexes namely, [Rh(fctca)(cod)] and [Rh(fctfa)(cod)], were tested for radiosensitizing potential against aerobic and hypoxic CHO cells in the presence of an 8 MV photon beam by the MTT assay adapted to our laboratory conditions. The ferrocene betadiketones co-ordinated to them, Hfctca and Hfctfa and the Ir compliment of [Rh(fctfa)(cod)] namely, [Ir(fctfa)(cod)] were also assessed by the MTT assay. Interestingly, neither the ferrocene nor the iridium complexes showed noteworthy sensitization, which suggests that the rhodium is responsible for the efficacy observed. The radiosensitizing potential of the most active complex, [Rh(fctfa)(cod)] and cisplatin were also confirmed by the use of the more traditional clonogenic assay. Not only did the MTT assay deliver results comparable to the clonogenic technique, but one of the complexes [Rh(fctfa)(cod)] showed radiosensitizing potential against hypoxic CHO cells, equal to that of cisplatin. The rhodium complex, [Rh(fctfa)(cod)] was also tested for radiosensitization properties against the CHO cell line in the presence of a p(66)/Be neutron beam. Results indicated that [Rh(fctfa)(cod)] sensitizes cells to radiation possibly by inhibition of cell inactivation mechanisms that are normally associated with repairable damage. Consequent work done on the flow cytometer where direct DNA damage after irradiation (8 MV photon beam) and drug treatment, was assessed on aerobic CHO cells by a technique adapted to our laboratory showed no significant increase in the forward angle scattered light (FSC) parameter which is an indication of radiation induced strand breaks. Furthermore, [Rh(fctfa)(cod)] showed a significantly greater increase in the side angle scattered light (SSC) parameter, which is an indication of the binding ability of the complex, compared to cisplatin, after treatment with different concentrations of the drugs. Results obtained from enumerating micronuclei frequencies after drug treatment and radiation confirmed that both cisplatin and [Rh(fctfa)(cod)] are more active under hypoxic conditions, with [Rh(fctfa)(cod)] responsible for more micronuclei per binucleated cell. In conclusion, I have established that [Rh(fctfa)(cod)] has a cytotoxic activity comparable to that of cisplatin and that it sensitizes preferentially hypoxic CHO cells to radiation in the clinically relevant dose range. I have also identified the probable action by which [Rh(fctfa)(cod)] sensitizes CHO cells to radiation as being inhibition of repair capacity. Furthermore, results suggest that this complex binds covalently to DNA base pairs. The complex [Rh (fctfa) (cod)] , has so far proven to possess interesting radiosensitizing potential which must be exploited for eventual therapeutic benefit. / Dissertation (MSc (Medical Physics))--University of Pretoria, 2007. / Medical Oncology / unrestricted

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This dissertation addresses the issue of robustness in proton therapy treatment planning for cancer treatment. Proton therapy is considered to be advantageous in treating most childhood cancers and certain adult cancers, including those of the skull base, spine and head and neck. Protons, unlike X-rays, have a finite range highly dependent on the electron density of the material they are traversing, resulting in a steep dose gradient at the distal edge of the Bragg peak. These characteristics, together with advancements in computation and technology have led to the ability to plan and deliver treatments with greater conformality, sparing normal tissue and organs at risk. Radiotherapy treatment plans aim to meet set dosimetric constraints, and meet them at every fraction. Plan robustness is a measure of deviation between the delivered dose distribution and the planned dose distribution. Due to the same characteristics that make protons advantageous, conventional means of using margins to create a Planning Target Volume (PTV) to ensure plan robustness are inadequate. Additional to this, without a PTV, a new method of analysing plan quality is required in proton therapy. My original contribution to the knowledge in this area is the demonstration of how site- and centre- specific robustness constraints can be established. Robustness constraints can be used both for proton plan analysis and to identify patients that require plans of greater individualisation. I have also used the daily volumetric imaging from patients previously treated with conventional radiotherapy to quantify range uncertainty from inter- and intra-fraction motion. These new methods of both quantifying and analysing the change in proton range in the patient can aid in the choice of beam directions, provide input into a multi- criteria optimisation algorithm or can be used as criteria to determine when adaptive planning may be required. This greater understanding in range uncertainty better informs the planner on how best to balance the trade-off between plan conformality and robustness in proton therapy. This research is directly relevant to furthering the knowledge base in light of HM Government pledging £250 million to build two proton centres in England, to treat NHS patients from 2018. Use of methods described in this dissertation will aid in the establishment of clear and pre-defined protocols for treating patients in the future.