M.Med., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Objectives Cancer of the cervix is one of the commonest cancers in South African females. Up to 30% of patients are HIV positive. The addition of chemotherapy to radiotherapy has been shown to significantly improve local control and survival and concurrent chemoradiation is the standard treatment for locally advanced cancer of the cervix. There is very limited literature available concerning the tolerance and efficacy of this treatment in HIV positive patients. This study aims to assess the acute toxicity of combined modality treatment in these patients. This study is part of a multicenter International Atomic Energy Agency sponsored study. Materials and methods Patients with FIGO stage IB2 to IIIB (without hydronephrosis) cervical cancer and who are HIV positive, were randomized to receive radiotherapy alone or chemo-radiation. All patients received 46 Gy in 23 fractions external beam radiation and high-dose-ratei brachytherapy 8 Gy x 3 fractions. Chemotherapy consisted of bolus Cisplatin 30mg/m2 weekly given concurrently with the radiotherapy. Acute treatment toxicity was documented weekly during treatment. Results 64 patients were recruited to the study. 31 patients were randomized to the chemoradiation arm and 33 patients to the radiation alone arm. Of the 64 patients recruited to the study, 6 in the chemoradiation arm and 5 in the radiation only arm did not receive any treatment and were therefore not evaluated. Stage IIB was the most common stage. The mean CD4 count was 410 in the chemoradiation arm vs. 358.4 in the radiation only arm at randomization. Only 6 patients were on antiretroviral therapy at start of treatment, 3 in each arm. The number of chemotherapy cycles received by patients in the chemoradiation arm ranged between 0 and 5 cycles. A total of 96 chemotherapy cycles were administered, with a median of 4 cycles per patient. Overall, at least 76% of patients received at least 4 cycles of chemotherapy. The full five intended courses of cisplatin were administered in 10 (40%) patients. Chemotherapy was not administered most commonly due to toxicity (renal, leucopaenia), other reasons being logistical and non compliance. The principle major adverse effects observed were leucopaenia and cutaneous reactions.

Neste trabalho apresentamos os resultados obtidos com um novo dosímetro de eletreto plano para uso em Radioterapia. O princípio de funcionamento do dosímetro de eletreto se baseia na utilização do campo do eletreto como o campo coletor de íons, em um sistema análogo ao da câmara de ionização, e ainda, corno um detector para a carga integrada. O modelo inicial do dosímetro possuía urna geometria cilíndrica. Através das curvas de calibração deste dosímetro, onde analisamos a sensibilidade, reprodutibilidade, estabilidade e, ainda, a dependência da sensibilidade com o volume e a pressão, concluímos que para aumentar a sua faixa útil de exposição, deveríamos construir um dosímetro com geometria plana. Estudamos a dependência da sensibilidade do dosímetro plano com as condições de carregamento do eletreto, volume da câmara e material da parede (alumínio, latão e aço inox) e os melhores resultados foram obtidos com o dosímetro de aço inox. Comparamos o comportamento deste sistema dosimétrico com um dosímetro Baldwin-Farmer, comumentemente usado em Radioterapia e verificamos que os resultados se mostraram satisfatórios. As características finais deste dosímetro são as seguintes: sensibilidade de 10-13C/R, volume de 0.20 cm3, reprodutibilidade de 5% e alcance máximo de exposição de 700 R. Finalmente, desenvolvemos um dosímetro múltiplo de eletreto para a medida da uniformidade do feixe de radiação para um aparelho de Cobaltoterapia. Os resultados da sua intercomparação com o dosímetro Baldwin-Farmer apresentaram uma variação máxima de 3%. / This work presents the results obtained with a new plane electret dosemeter for use in Radiotherapy. The working principle of the electrets dosemeter in based on the use for the electret field the ion collecting field, similarly to an ionization chamber, and as charge integrator detector. The dosemeter had, initially, a cylindrical geometry. The results attained with its calibration curve concerning the sensitivity, the stability and the reproducibility lead to changes in the dosimeter geometry. A plane geometry dosemeter was built in order to increase the useful exposure range. The plane dosemeter sensitivity dependence was measured versus the electrets charging conditions, the chamber volume and wall material (aluminium, brass, and stainless steel). The stainless steel dosemeter showed the best results. This dosemeter has the following characteristics: sensitivity 10-13C/R, volume 0.20 cm3, reproducibility 5%, and maximum exposure range 700 R. Compared to the Baldwin-Farmer dosemeter, this results are fairly good. A multiple electret dosemeter was developed to monitor the uniformity of the radiation beam for a Cobalt teletherapy unit. The intercomparasion with the Baldwin-Farmer unit presented a maximum variation of 3%.

Em radioterapia externa, uma nova técnica chamada terapia de radiação de intensidade modulada - IMRT - permite delinear a dose de radiação em imagens de 2 ou 3 dimensões, delimitando de forma bastante precisa e não necessariamente uniforme a região a ser irradiada. Assim, ao mesmo tempo que o tumor é irradiado, é possível evitar a irradiação aos tecidos vizinhos íntegros (sãos), limitando os efeitos secundários do tratamento. Para que a radioterapia externa tenha sucesso usando a técnica IMRT, é fundamental delinear previamente de forma precisa o tumor e os órgãos sãos que devem ser protegidos da radiação, garantindo assim a dose exata de radiação nos volumes alvos. O objetivo desta tese é fornecer ferramentas que sejam adequadas ao delineamento automático de estruturas de interesse e à radioterapia adaptativa para tumores da região da cabeça e do pescoço. Atualmente, a segmentação de estruturas de interesse, tais como os órgãos em risco e as regiões de propagação tumoral, é feita manualmente. Esta é uma tarefa que demanda bastante tempo de um especialista, além de ser tediosa. Além do mais, o planejamento em radioterapia é feito baseado na imagem adquirida na semana do pré-tratamento, onde é calculada a dose. Normalmente o tratamento ocorre em várias semanas, porém a dose estimada no início do tratamento é a mesma para todas as outras semanas do tratamento. Calcular a dose e mantê-la nas demais semanas é uma simplificação que não corresponde à realidade, já que ocorrem mudanças anatômicas no paciente ao longo do tratamento. Estas mudanças ocorrem devido ao encolhimento do tumor e ao possível emagrecimento do paciente, provocando alterações anatômicas locais e globais. As contribuições desta tese visam solucionar e avançar nestes problemas e são apresentadas em dois eixos. No primeiro eixo, é proposta uma metodologia para escolher uma anatomia que seja representativa da população, anatomia esta chamada de atlas. O registro do atlas na imagem do paciente permite que estruturas de interesse sejam segmentadas automaticamente, acelerando o processo de delineamento e tornando-o mais robusto. A segunda contribuição desta tese é voltada à radioterapia adaptativa. Para que a dose estimada na primeira semana seja adaptada às modificações anatômicas, é necessária a utilização de métodos de registro não-rígidos. Portanto, nesta etapa é feita uma avaliação e adaptação dos métodos de registros de forma que a região do tumor esteja bem alinhada. / Intensity Modulated Radiotherapy (IMRT) is a new technique enabling the delineation of the 3D radiation dose. It allows to delineate a radiation zone of almost any shape and to modulate the beam intensity inside the target. If IMRT enables to constrain the radiation plan in the beam delivery as well as in the protection of important functional areas (e.g. spinal cord), it also raises the issues of adequacy and accuracy of the selection and delineation of the target volumes. The purpose of this thesis is to provide tools to automatic delineation of the regions of interest and also to adaptive radiotherapy treatment for tumors located in the head and neck region. The delineation in the patient computed tomography image of the tumor volume and organs to be protected is currently performed by an expert who delineates slice by slice the contours of interest. This task is highly time-consuming and requires experts’ knowledge. Moreover, the planning process in radiotherapy typically involves the acquisition of a unique set of computed tomography images in treatment position on which target volumes (TVs) and normal structures are delineated, and which are used for dose calculation. Restricting the delineation of these regions of interest based solely on pre-treatment images is an oversimplification as it is only a snapshot of the patient´s anatomy at a given time. Shrinkage of the tumor and modification of the patient anatomy at large (e.g. due to weight loss) may indeed occur within the several weeks’ duration of a typical treatment. The main contributions of this thesis aim to advance in the solution to these issues and are presented in two axes. In the first one, it is proposed a methodology to choose an image with the most representative anatomy of a population; such image is called Atlas. The registration of the atlas into a new image of the patient allows to automatically segment the structures of interest, speeding up the delineation process and making it more robust. The second contribution of this thesis is focused on the adaptive radiotherapy. In order to adjust the estimated dose to the anatomical modifications, it is fundamental to have non-rigid registration algorithms. So, the evaluation and adaptation of non-rigid registration methods are required, addressing especially the alignment of the tumor’s region among different moments of the treatment.

Atualmente a maior parte dos tratamentos radioterápicos é feita através de irradiações com feixes de fótons de alta energia. Esses feixes se originam em fontes radioativas (de nuclídeos como o cobalto 60) ou são gerados em aceleradores lineares de elétrons. Para as medidas dosimétricas nesses feixes, uma das técnicas mais utilizada é a termoluminescência (TL) e, para a correta utilização dos dosímetros termoluminescentes (TLDs), é necessário conhecer suas características dosimétricas como, por exemplo, a variação da sua resposta com a energia do feixe de radiação. O objetivo desse trabalho foi estudar essa dependência energética da resposta TL de diversos materiais quando irradiados em feixes de fótons de alta energia. Para isso, foram obtidas curvas de resposta TL em função da dose absorvida em água para os LDs de LiF:Mg, Ti (TLD-100), fluorita natural brasileira, CaSO4:Dy, Mg2SiO4:Tb e l2O3:C irradiados em feixes gama de 60Co e de raios X de aceleradores lineares com potenciais de aceleração nominais de 6, 10, 15 e 18 MV. O estudo foi feito em uma faixa de doses equivalente à utilizada em fracionamentos padrão de tratamentos de radioterapia e os resultados demonstram que, nessas condições, não há variação maior que 3% na resposta TL em função da energia dos fótons. A relação entre a deposição e doses nos TLDs e a deposição de doses na água em função da variação da energia oi estudada por simulação de Monte Carlo (MC), através do código PENELOPE, e os resultados foram coerentes com os resultados experimentais. Os TLDs também foram irradiados com nêutrons térmicos e epitérmicos e apresentaram sensibilidade a esse tipo de radiação. No entanto, a coerência dos resultados experimentais e de MC (que não levaram em conta a presença de nêutrons), o estudo da variação da sensibilidade relativa com a energia e a análise das curvas de emissão dos TLDs levam à conclusão e que a influência na resposta TL devida a nêutrons que contaminam os feixes de fótons estudados, é desprezível para todos os materiais. Os resultados desse trabalho indicam que, para a faixa de doses e energias utilizadas rotineiramente na radioterapia, os TLDs de LiF:Mg, Ti (TLD-100), fluorita natural brasileira, CaSO4:Dy, Mg2SiO4:Tb e Al2O3:C podem ser utilizados sem a aplicação de fatores de correção para a energia do feixe. / Currently the majority of radiotherapy treatments are done by irradiation with high energy photon beams. These beams are emitted by radioactive sources (of nuclides such as cobalt 60) or generated in electron linear accelerators. For dosimetric measurements on these beams, one of the most used techniques is the thermoluminescence (TL). For the correct use of the thermoluminescent dosimeters (TLDs), it is necessary to know their dosimetric properties like, for example, the variation of their response with the energy of the radiation beam. The purpose of this study was to assess the energy response of various TL materials when irradiated with high energy photon beams. So, curves relating the TL response and absorbed dose to water were obtained for LiF:Mg, Ti (TLD-100), Brazilian natural fluorite, CaSO4:Dy, g2SiO4:Tb and Al2O3:C TLDs irradiated with gamma rays from a 60Co source and linear accelerator X ray beams with nominal accelerating potential of 6, 10, 15 and 18 MV. The study was done in a dose range similar to that used in standard fractionated radiotherapy treatments and the results show that under these conditions, there is no variation larger than 3% in the TL response as a function of photon energy. The relationship between the dose deposition in the TLD and the dose deposition in water in function of the photon energy was studied by Monte Carlo method (MC), using the PENELOPE code system, and the results were consistent with the experimental outcomes. The TLDs were also irradiated with thermal and epithermal neutrons and proved to be sensitive to them. However, the consistency of the experimental and MC results (which did not take into account the presence of neutrons), the study of the variation in TL relative sensitivity with the beam energy, and the TLD glow curve shape analysis lead to the conclusion that the influence on TL response due to neutron contamination in the therapeutic photon beams is negligible for all materials. The results indicate that for the range of doses and energies used routinely in radiotherapy, the LiF:Mg, Ti (TLD-100), Brazilian natural fluorite, CaSO4:Dy, Mg2SiO4:Tb and Al2O3:C TLDs can be used without applying any correction factors for the beam energy.

O Relatório Mundial do Câncer, a Agência Internacional Para Pesquisa no Câncer e a Organização Mundial da Saúde estimam que, a cada ano há 12,4 milhões de novos casos de câncer no mundo, havendo 7,6 milhões de mortes causadas pela doença, onde para os homens o mais recorrente é o câncer de próstata. Por isso, o tratamento de câncer de próstata, neste caso, por radioterapia deve apresentar elevada precisão. Um complicador para tal precisão pode ser a presença de próteses metálicas no fêmur e na pélvis, podendo ser unilateral ou bilateral. O objetivo deste trabalho foi analisar e comparar o tratamento radioterápico de próstata para três situações diferentes, com duas próteses, com uma prótese e sem nenhuma prótese através da dosimetria por Ressonância Paramagnética (EPR) utilizando o aminoácido alanina com dosímetro, que se baseia na determinação de radicais livres produzidos pela interação entre a radiação e a alanina através do registro do espectro da alanina irradiada. Para tal análise foi construído um simulador físico (phantom), com as medidas reais de um ser humano, feito de acrílico e água, simulando o tecido mole, e ossos humanos. Na região da próstata foi feita uma abertura cilíndrica onde foram inseridos os dosímetros de alanina compostos 95% de DL-alanina e 5% de Polivinil Álcool (PVA) com 3mm de diâmetro, 4 mm de comprimento e massa de 0,05 g. O phantom foi irradiado para cada situação, nas condições de tratamento em um acelerador linear Oncor Plus da Siemens com feixe de raios X de 6MV para quatro campos 10x10cm2 e uma dose de 2 Gy, onde as mesmas condições foram utilizadas para a calibração dos dosímetros. Os dosímetros foram analisados em um espectrômetro de banda X JEOL JES-FA200 (9.5 GHz). Através da curva de calibração e a amplitude da linha central do espectro foi possível calcular a dose obtida em cada dosímetro de DL-alanina obtendo uma variação de até 6,15% para as medidas da dose prescrita de 2 Gy. Os resultados mostraram-se semelhantes para as três situações estudadas, assim como calculado no sistema de planejamento. / The World Cancer Report, the International Agency for Research on Cancer and the World Health Organization estimates that each year there are 12.4 million new cases of cancer worldwide, with 7.6 million deaths from the disease, for which men is the most recurrent prostate cancer. Therefore, the treatment of prostate cancer, in this case by radiotherapy should have a high accuracy. A complicating factor for such precision may be the presence of metallic prosthesis in the femur and pelvis and may be unilateral or bilateral. The objective of this study was to analyze and compare the radiotherapy of prostate for three different situations, with two prostheses, with one prosthesis and without a prosthesis through dosimetry Paramagnetic Resonance (EPR) using the amino acid alanine with dosimeter, which is based on determining free radicals produced by the interaction between radiation and alanine by recording the spectrum of irradiated alanine. For this analysis we built a physical simulator (phantom), with the real measurements of a human being, made of acrylic and water, simulating soft tissue, and human bones. In the region of the prostate was made a cylindrical opening in which the dosimeters were inserted alanine compounds 95% DL-alanine and 5% Polyvinyl Alcohol (PVA) with 3mm diameter, 4 mm in length and mass of 0.05 g. The phantom was irradiated for each situation, the conditions of treatment in a linear accelerator Oncor Plus Siemens X-ray beam with 6mV for four fields of 10x10cm2 and a dose of 2 Gy, where the same conditions were used for calibration of the dosimeter. The dosimeters were analyzed in a JEOL X-band spectrometer JES-FA200 (9.5 GHz). Through the calibration curve and the amplitude of the centerline of the spectrum was possible to calculate the dose obtained in each of DL-alanine dosimeter obtaining a variation of up to 6.15% for the measurements of the prescribed dose of 2 Gy. The results were similar for the three cases studied, as calculated in the planning system.

Bibliography: leaves 241-250. A multileaf collimator for radiation therapy has been designed that splits each leaf bank into two vertically displaced assemblies or levels with each level consisting of alternate leaves and leaf spaces. The radiation profiles transmitted for image formation through the collimator design were investigated to examine their dependence on the collimator design features.

Radium needles that were once implanted into tumours as a cancer treatment are now obsolete and constitute a radioactive waste problem, as their half-life is 1600 years. The reduction of radium by photonuclear transmutation by bombarding Ra-226 with high-energy photons from a medical linac has been investigated. The irradiated needles would then be processed to remove the Ac-225, which can then be used for .Targeted Alpha Therapy. (TAT) of cancer. This project has the potential to slowly reduce obsolete radioactive material, and displace future expensive importation of Ac-225 from Russia, Germany (Institute for Transuranium Elements - ITU) and the US in the years ahead. This thesis progresses through a number of stages and begins by providing a background to the usefulness of Ac-225 as an alpha emitter, some of the equipment used in the experimental work such as linear accelerators and detectors, as well as the initialisation of a process whereby a reliable source of high-grade radium is secured, suitable equipment obtained, followed by a series of experiments leading to the production of the desired product, actinium and bismuth. The second stage of this study involved the formulation of a theoretical model in which the bremsstrahlung photon spectrum at 18 MV linac electron energy is convoluted with the corresponding photonuclear cross sections of Ra- 226. This enabled the total integrated yield of Ra-225 and its daughter product Ac-225 to be obtained. The third stage of this study ties the theoretical and experimental work together by presenting the results of a number of experiments performed on radium sources. These experiments were performed over a period of about three years using a variety of detectors in a hospital setting. These experiments, as presented in this thesis, demonstrate that Ac-225 can be produced in small quantities by a medical linac or in commercial quantities by the use of a high-powered linac or cyclotron, thereby, ensuring a reliable supply of Ra-225 for TAT and also reducing the radium waste product. / Doctor of Philosophy

From one treatment to the next, considerable effort is made to accurately position radiotherapy patients according to their treatment plans. However, some variation is unavoidable. The target volume and the organs at risk may also move within the patient and/or change shape during the treatment. Thus, it is important to be able to verify the success of the treatment by determining the position of patient and the dose deposited in the patient at each fraction. One possibility to achieve this, particularly when equipment, time and budgets are limited, would be to collect limited information while the patient is on the treatment couch. This research was aimed to develop a method for optimum beam position determination, for each patient-specific case. The optimized beam positions would balance the both treatment planning and image reconstruction, so that the patient???s image can be obtained during the treatment delivery using the information collected from the same angles as used for treatment. This will allow verification of the dose deposited in the patient for every fraction. Using a limited number of angles for image reconstruction, the dose to the patient can be minimized. This work has two major parts, beam position optimization for image reconstruction and beam position optimization for treatment planning. These two optimizations are then combined to obtain the optimum beam position for both image reconstruction and treatment planning. An objective function, projection correlation, was developed to investigate the image reconstruction method using limited information. Another objective function, the average optimization quality factor, was also introduced to optimize beam positions for treatment planning. Two optimization methods, the gradient descent method and the simulated annealing based on these objective functions were used to determine the beam angles. The results show that the projection correlation presents several advantages. It can be applied without any iterations, and it produces a fast algorithm. The present research will allow selection of the optimum beam positions without excessive computational cost for treatment planning and imaging. By combining the projection correlation and the average optimization quality factor together with more advanced image reconstruction software this could potentially be used in a clinical environment.

The measurement of productivity in health care is difficult. Studies in various specialty disciplines of medicine have identified that the variation in complexities (casemix) between departments or hospitals will vary and therefore will affect any basic productivity statistics that are produced. Radiation oncology is a discipline of medicine where no such studies into radiotherapy casemix variations and the effect that these may have on productivity measures have been performed, despite the high capital expenditure involved in the delivery of radiotherapy. Radiation oncology productivity on linear accelerators is currently measured by the number of patients treated or number of treatment fields treated per unit time (usually per hour). These statistics have been collected for many years and productivity assessments were made on the variations in these statistics that exist between departments. However, these statistics do not consider the variations in casemix that occur between departments. These complexity differences may be quite marked and therefore may strongly influence the ability of a department to achieve a high patient or treatment field throughput. This may be seen as 'reduced productivity' with no consideration of the complexity of the caseload seen in the department. In addition, future technological changes that improve patient outcome may be introduced. These changes may make treatment more complex. Using older measures of productivity such as fields per hour or patients per hour will not consider these technological changes and the subsequent changes in complexity and hence departments may be seen as less productive in the future using current methods of analysis unless a more valid measure of productivity that considers complexity variations is introduced. There have only been 3 previous attempts at developing measures of linear accelerator productivity. Each of these models have been developed empirically and have not been clinically validated. No previous attempts have been made in determining a scientifically-derived complexity model that considers the variations in treatment technique. This thesis describes research performed between 1995 and 2001. This research study???s primary aims were to study the factors that affect radiotherapy treatment time and treatment complexity and to develop a model of linear accelerator productivity that does consider complexity variations in radiotherapy treatment delivery. This model is called the Basic Treatment Equivalent (B.T.E.). This series of trials examines the old models of linear accelerator productivity, describes the derivation and validation of the BTE model both in Australasia and the United Kingdom, identifies the factors that contribute to treatment time and treatment complexity, describes the development of a pilot model of productivity of gynaecological brachytherapy and outpatient chemotherapy using similar BTE methodology, discusses the potential uses of the BTE model, recent independent reviews of BTE by other groups, and the advantages and disadvantages of using such a model. This research has shown that it is possible to identify the various factors that contribute to treatment time and treatment complexity and to derive a model of linear accelerator productivity that considers the variations in complexity. The BTE model has been clinically validated in Australia, New Zealand and a couple of departments in the United Kingdom and Canada and has been adopted as a new measure by various groups. It requires regular updating to maintain currency particularly as there are frequent improvements in radiation treatment technology. Future studies should identify the differences these technological enhancements make to productivity. The BTE derived from outpatient chemotherapy delivery and gynaecological brachytherapy delivery shows promise although these models require further research with the assistance of other departments.

Intensity Modulated Radiation Therapy (IMRT) is a modern radiotherapy treatment technique used to obtain highly conformal dose distributions. The delivery of IMRT is commonly achieved through the use of a multileaf collimator (MLC). One of the hindrances at present to the widespread use of IMRT is the increased time required for its planning, delivery and verification. In this thesis one particular method of MLC based IMRT, known as Static Multileaf Collimator based IMRT (SMLC-IMRT), has been studied along with methods for improving it???s delivery efficiency. The properties of an MLC commonly used in SMLC-IMRT have been characterised. The potential ramifications of these properties on the dosimetric accuracy of the delivered IMRT field were also investigated. An Interactive Leaf Sequencing (ILS) program was developed that allowed for the manipulation and processing of intensity maps using a variety of methods. The objective of each method was to improve the delivery efficiency whilst maintaining the dosimetric quality of the IMRT treatment. The different methods investigated were collimator angle optimisation, filtration, and intensity level optimisation. The collimator was optimised by identifying the angle at which the minimum monitor unit???s (MU???s) were required when using a sliding-window delivery method. A Savitzky-Golay filter was applied to random intensity maps and suitable filtration parameters identified for filtering clinical IMRT fields, and the intensity levels were optimised based on a deviation threshold. The deviation threshold identified the acceptable level of difference tolerable between the original and modified intensity map. Several IMRT cases were investigated and the impact of each the methods on MU???s, segments and dose distribution observed. As the complexity of IMRT fields increases the dosimetric impact of the MLC properties increases. Complex SMLC-IMRT fields require longer delivery times due to the increased number of MU???s and segments. Collimator optimisation was shown to be a fast and effective means of improving delivery efficiency with negligible dosimetric change to the optimised plan. Modifying intensity maps by applying a filter and optimising the intensity levels did reduce the complexity and improve the delivery efficiency, but also required a dosimetric compromise of the optimised plan.