O sarcoma de Ewing é uma neoplasia maligna agressiva que acomete ossos e tecidos moles com maior frequência em crianças e adolescentes. O tratamento consta de quimioterapia de indução, seguida pelo controle local da doença (cirurgia, cirurgia associada à radioterapia, ou apenas radioterapia), e quimioterapia de consolidação. A introdução da quimioterapia possibilitou aumento significativo na sobrevida dos pacientes nas últimas décadas. Por outro lado, o impacto da modalidade de controle local ainda não está bem estabelecido. Estudos observacionais têm demonstrado superioridade do tratamento cirúrgico em relação à radioterapia isolada, no entanto, são limitados os estudos prospectivos que confirmam esta diferença. O objetivo deste estudo é avaliar o impacto da modalidade de tratamento local nos desfechos oncológicos, bem como descrever o perfil clínico-epidemiológico de portadores de sarcoma de Ewing ósseo não-metastático. Os dados foram coletados em 15 instituições no período entre 2003 e 2010 e fazem parte do primeiro estudo do Grupo Colaborativo Brasileiro para Tratamento dos Tumores da Família Ewing (EWING I). Dos 73 pacientes incluídos, 47 foram tratados com cirurgia isolada, 13 receberam cirurgia associada à radioterapia, e 13 apenas radioterapia. O seguimento médio foi de 4,5 anos (2,3 até 6,7 anos) e a sobrevida geral e livre de eventos foi de 63,3 e 62,1 por cento em 5 anos, respectivamente. A falha do tratamento local foi de 0 (zero) por cento para a modalidade de cirurgia associada à radioterapia, 6,5 por cento para cirurgia isolada, e 10 por cento para radioterapia (p=0,5). A sobrevida dos pacientes submetidos à radioterapia isolada foi significativamente inferior à sobrevida dos tratados com cirurgia e com cirurgia associada a radioterapia (30,8 versus 71,7 versus 64,1 por cento, respectivamente). Concluiu-se que não houve diferença em termos de falha local de acordo com a modalidade de tratamento empregada, no entanto houve diferença significativa em termos de sobrevida. Apesar dos resultados cirúrgicos superiores, a radioterapia isolada ainda apresenta papel fundamental no tratamento de casos selecionados. / Ewing sarcoma is a small round cell malignancy of bone and soft tissue that usually occurs in children and adolescents. Current treatment includes induction chemotherapy, local control of the primary tumor (surgery, surgery plus radiotherapy, or radiotherapy) and consolidation chemotherapy. The introduction of chemotherapy has improved significantly the oncologic outcomes in Ewing sarcoma. On the other hand, the impact of the local control modality has not been established. Surgery alone or in combination with radiation has traditionally been considered a good choice for resectable ES, while unresectable tumors have been treated with definitive radiotherapy. Despite the results from a few trials and observational studies, there is no consistent knowledge about the local control modality in ES outcomes. The present study aims to evaluate the impact of the local control modality in the oncologic outcomes, as well as to describe the clinical features of the patients with localized Ewing sarcoma of the bone. The data were collected between 2003 and 2010 in 15 hospitals and were part of the first Brazilian Collaborative Group for the Treatment of the Ewing Sarcoma Family Tumors (EWING 1). From 73 patients (median age 12.8 years old), 47 were treated with surgery, 13 with surgery plus radiotherapy, and 13 with definitive radiotherapy. Median follow up was 4.5 years (2.3 to 6.7 years) and the overall and event-free survival 63.3 and 62.1 percent in 5 years, respectively. The local control failure was 0 percent for surgery plus radiotherapy, 6.5 percent for surgery, and 10 percent for radiotherapy (p=.5). The survival of the patients treated with radiotherapy was significantly worse than those treated with surgery and surgery plus radiotherapy (30.8 versus 71.7 versus 64.1 percent, respectively). In conclusion, there was no significant difference in local failure according to the modality of treatment, but there was significant difference in survival rates. Despite the better outcomes in individuals treated with surgery, the radiotherapy modality has still an important role in selected patients.

Radiotherapy planning involves the calculation of dose deposition throughout the patient, based upon quantitative electron density images from computed tomography (CT) scans taken before treatment. Cone beam CT (CBCT), consisting of a point source and flat panel detector, is often built onto radiotherapy delivery machines and used during a treatment session to ensure alignment of the patient to the plan. If the plan could be recalculated throughout the course of treatment, then margins of uncertainty and toxicity to healthy tissues could be reduced. CBCT reconstructions are normally too poor to be used as the basis of planning however, due to their insufficient sampling, beam hardening and high level of scatter. In this work, we investigate reconstruction techniques to enable dose calculation from CBCT. Firstly, we develop an iterative method for directly inferring electron density from the raw X-ray measurements, which is robust to both low doses and polyenergetic artefacts from hard bone and metallic implants. Secondly, we supplement this with a fast integrated scatter model, also able to take into account the polyenergetic nature of the diagnostic X-ray source. Finally, we demonstrate the ability to provide accurate dose calculation using our methodology from numerical and physical experiments. Not only does this unlock the capability to perform CBCT radiotherapy planning, offering more targeted and less toxic treatment, but the developed techniques are also applicable and beneficial for many other CT applications.

O objetivo deste estudo foi avaliar, in vitro, a influência da radioterapia na resistência de união (RU) do material obturador à dentina e na interface adesiva de caninos superiores obturados com cimento AH Plus e MTA Fillapex, por meio de teste de cisalhamento por extrusão (push-out) e microscopia eletrônica de varredura (MEV). Trinta e dois caninos superiores foram selecionados e distribuídos em 2 grupos (n=16) de acordo com a irradiação: Grupo I - Não irradiados e Grupo II - Irradiados, submetidos à radioterapia com raios-X com 6 MV em frações de 2 Gy, por 5 dias consecutivos, com 30 ciclos, durante 6 semanas, perfazendo 60 Gy. Após a irradiação, o preparo biomecânico dos dentes foi realizado utilizando o sistema Reciproc (R50) e irrigação com hipoclorito de sódio a 1%. Cada grupo foi subdividido de acordo com o cimento endodôntico utilizado (n=8): Subgrupo A - AH Plus; e Subgrupo B - MTA Fillapex e obturados com a técnica do cone único. Decorrido o tempo de endurecimento dos cimentos, os dentes foram transversalmente seccionados em slices de 1 mm de espessura, obtendo-se 3 slices de cada terço da raiz. O primeiro slice no sentido coroa-ápice de cada terço foi selecionado para avaliar a RU por meio do teste de push-out com velocidade de 0,5 mm/min e posterior análise do padrão de falhas por meio de estereomicroscópio. Para análise por MEV, foram selecionados aleatoriamente dois dentes de cada grupo, cujos slices (um de cada terço) foram preparados utilizando-se dois protocolos previamente à metalização. Para a análise da interface dentina/material obturador foi utilizado o protocolo de desidratação e para análise da penetrabilidade do cimento foi utilizado o protocolo de descalcificação superficial. Após metalização, os slices foram avaliados qualitativamente com aumentos de 75, 100 e 500x. Os dados (MPa) foram submetidos à análise estatística pelos testes de ANOVA e Tukey (p<0,0001). Os espécimes irradiados (0,71±0,20) apresentaram os menos valores de RU (p<0,0001) independente do cimento utilizado, e, quando comparados os cimentos, os espécimes obturados com MTA Fillapex (0,70±0,18) apresentaram valores menores que os obtidos com o AH Plus (1,00±0,27) (p<0,0001). O terço cervical apresentou valores superiores entre os terços das regiões analisadas dentro de cada grupo diminuindo em direção apical (p<0,0001). Houve maior ocorrência de falhas adesivas para o cimento AH Plus em todos os terços avaliados nos espécimes irradiados. Na análise qualitativa em MEV, observou-se maior quantidade de gaps na interface cimento/dentina nos espécimes irradiados quando comparados aos não irradiados. De modo geral, para os espécimes obturados com cimento AH Plus, foi possível observar a presença de densas áreas de tags resinosos, longos, contínuos e regularmente distribuídos, diferentemente dos obturados com MTA Fillapex que se apresentaram menores, menos numerosos e dispostos de forma irregular. Concluiu-se que a radioterapia diminuiu a RU dos cimentos à dentina, independente do cimento obturador utilizado, sendo que o MTA Fillapex propiciou RU menor que o AH Plus, tanto nos dentes irradiados como nos não irradiados, com formação de gaps na interface cimento/dentina e menor formação de tags resinosos / The purpose of this in vitro study was to evaluate the influence of the radiotherapy on the bond strength (BS) of the filling material to dentin and the adhesive interface of superior canines filled with AH Plus and MTA Fillapex using the bond strength test (push-out) and the scanning electron microscopy (SEM). Thirty-two superior canines were selected and divided into 2 groups (n=16) according to the irradiation: Group I - Non-irradiated and Group II - Irradiated, submitted to a X-Ray of 6 MV regimen in fractions of 2 Gy, for 5 consecutive days, 30 cycles during 6 weeks, totalizing 60 Gy. After the irradiation, biomechanical preparation of the teeth was performed with the Reciproc system (R50) irrigated with 1% sodium hypochlorite. Each group was then subdivided according the sealer (n=8): Subgroup A - AH Plus; and Subgroup B - MTA Fillapex and the single-cone technique was used. Elapsed the setting time of the sealers, the teeth were transversally sectioned in slices of ±1 mm thickness, obtaining 3 slices from each root third. The first slice in the crown-apex direction of each third was selected for the BS evaluation at a speed of 0.5 mm/min and the posterior analysis of the pattern failure with a stereomicroscope was performed. For the SEM analysis, two teeth of each group were randomly selected, in which, a slice of each third was prepared using two different protocols prior the metallization. For the dentin/filling material interface analysis a protocol of dehydration was used and for the sealer penetrability a superficial decalcification protocol was performed. After the metallization, the slices were qualitatively evaluated at 75, 100 and 500x magnifications. Data (MPa) was submitted to the statistical analysis by the ANOVA and Tukey tests (p<0.0001). The irradiated specimens (0.71±0.20) had lower BS values (p<0.0001) independently of the used sealer, and when compared, the sealers of the specimens filled with MTA Fillapex (0.70±0.18) showed lower values than the ones filled with AH Plus (1.00±0.27) (p<0.0001).The cervical third had higher values between the analysed regions of the thirds in each group, decreasing towards apical direction (P<0.0001). There was a higher occurrence of adhesive failures for the AH Plus sealer in every evaluated third of the irradiated specimens. In the qualitative analysis of the SEM, a higher amount of gaps was observed in the dentin/filling material interface of the irradiated specimens compared to the non-irradiated specimens. In general, for the specimens filled with AH Plus, it was possible to notice the presence of extensive areas with long and regularly distributed resin tags, them being, different from the specimens filled with MTA Fillapex, which were less frequent and irregularly disposed. It can be concluded that radiotherapy decreased the BS values of the sealers to the dentin, independently of the sealer, with lower values in the teeth filled with MTA Fillapex compared to AH Plus, both for the irradiated as well as for the non-irradiated teeth with formation of gaps in the interface sealer/dentin and the decrease formation of resin tags

O objetivo primordial da Radioterapia é fornecer ao tumor uma dose de radiação suficientemente alta e uniformemente distribuída, de forma a poupar os tecidos adjacentes saudáveis dos efeitos ela radiação. Alcançar esse objetivo em sua plenitude é muito difícil devido à vários fatores, como por exemplo uma determinação eficiente do volume a ser tratado (através ela aquisição ele imagens tomográficas ela localização elo tumor no corpo) e também a realização eficaz da distribuição da. dose de radiação (que deve ser tridimensionalmente uniforme e alta o suficiente para erradicar a doença). Atualmente, a técnica de intensidade modulada do feixe (IMRT) usada na Radioterapia Convencional desempenha um avanço importante para o tratamento de tumores situados perto de estruturas anatômicas complexas, como é o caso dos tumores de próstata e de cabeça e pescoço. Essa moderna técnica conformacional já é aplicada nos tratamentos de tumores em vários hospitais nacionais, e citamos, como exemplo, o Hospital Sírio e Libanês, em São Paulo. No entanto, em países como os Estados Unidos, a Alemanha e o Japão, a radioterapia com partículas pesadas carregadas, como prótons c íons de carbono, tem sido desenvolvida há vários anos e demonstra sucesso absoluto no tratamento localizado ele tumores devido a deposição de energia característica dos feixes hadrônicos. A Hadronterapia, modalidade de tratamento ainda desconhecida no Brasil, é o objeto desse trabalho. Nele apresentamos a física básica envolvida no fenômeno da perda de energia dos projéteis, revisamos a dedução da conhecida fórmula ele Bethe-Bloch e, utilizando uma aproximação semi-clássica para obtenção da seção de choque da reação, obtemos os efeitos de uma interação nuclear considerada como uma perturbação à interação coulombiana dominante. Aplicamos também o modelo estatístico de Goldhaber para o cálculo dos efeitos da fragmentação nuclear induzida pelo projétil e, partindo de conceitos utilizados em astrofísica., calculamos a taxa de reação para estimar, quantitativamente, a influência da temperatura. na região do tumor neste processo. / The aim of radiation therapy is to deliver the dose as high and as uniform as possible to diseased tissue sparing all the other parts, that is healthy and critical tissues, without causing unwanted and unnecessary side effects for the patient. Difficults to achieve this goal start with the determination of the three­ dimensional volumes of interest and end up in realizing a three-dimensional uniform and maximal as possible, the dose distribution. The technique of intensity-modulated radiotherapy (IMRT) as form of conformation in conventional radiation therapy is a real revolution. On the other hand, the use of therapeutic charged particles, as protons and carbon íons, is the technology of the actual future which is really the challenge in conformation of dose to targets, thanks to energy deposition characteristics of hadronic beams. The aim of this work is to review the basic physics concerning the treatment of localized tumors with charged particles by applying a semi-classical approach to obtain a dispersion in the equation of energy loss, originally derived by Hans Bethe and Felix Bloch. On a second moment we use statistical methods (Goldhaber statistic model) to estimate the energy of fragment after nuclear fragmentation processes and, in addition, we obtain a expression for the nuclear reaction rate to introduce how the temperature on tumor region would affect it.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science, 2017 / Aim: The aim of this study was to quantify random and systematic setup errors in a population of head and neck cancer patients for the purposes of evaluating departmental positioning and immobilization techniques, verification and treatment protocols, as well as validating the treatment margins used. Methods and Materials: All patients had more than one phase of radiation, each consisting of different megavoltage photon field arrangements. Some phases were also treated with electron fields in addition to the photon fields. Random and systematic setup errors in all three principal directions were calculated for two groups of patients, using record and verify system couch position data. For one group (20 patients) the positioning and immobilization device system was mechanically localized to the treatment couch, and for the other group (38 patients), it was visually centered on the treatment couch. Within both groups of patients, the patient position was either verified online with portal imaging or verified offline on a conventional radiotherapy simulator. Results: For the patient group treated with the base plate visually centered on the treatment table the population random and systematic setup errors calculated for the photon fields were only indicative of setup uncertainties in the anterior-posterior direction. For the patient group treated with the base plate localized to the treatment couch, the population random and systematic setup errors were found to be within the 5 mm clinical to planning target volume expansion margin used at Livingstone Hospital. Due to treatment couch position differences from fraction to fraction, setup errors made during this study could not reliably be determined for electron field treatments Conclusions: Results indicate that the base plate should be localized to the treatment couch when calculating random and systematic setup errors for photon fields using the couch position as a surrogate for patient position. For this method to be used to calculate setup errors for electron fields, shielding should always be fastened to the same position at the endface of the applicator. Offline and online verification did not significantly influence systematic setup errors. / XL2018

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.

One of the greatest challenges in achieving accurate positioning in head and neck radiotherapy is that the anatomy at and above the cervical spine does not act as a single, mechanically rigid body. Current immobilization techniques contain residual uncertainties that are especially present in the lower neck that cannot be reduced by setting up to any single landmark. The work presented describes the development of a radiotherapy friendly mostly-plastic 6D robotic platform for positioning independent landmarks, (i.e., allowing remote, independent positioning of the skull relative to landmarks in the thorax), including analysis of kinematics, stress, radiographic compatibility, trajectory planning, physical construction, and phantom measurements of correction accuracy. No major component of the system within the field of imaging or treatment had a measured attenuation value greater than 250 HU, showing compatibility with x-ray-based imaging techniques. Relative to arbitrary overall setup errors of the head (min = 1.1 mm, max = 5.2 mm vector error) the robotic platform corrected the position down to a residual overall error of 0.75 mm +/- 0.33 mm over 15 cases as measured with optical tracking. This device shows the potential for providing reductions to dose margins in head and neck therapy cases, while also reducing setup time and effort.

External beam radiation therapy for prostate cancer can result in urinary, sexual, and rectal side effects, often impairing quality of life. A polyethylene glycol-based product, SpaceOAR hydrogel (SOH), implanted into the connective tissue between prostate gland and rectum can significantly reduce the dose received by the rectum and hence risk of rectal toxicity. The optimal way to manage the hydrogel and rectal structures for plan optimization is therefore of interest. A retrospective planning study was completed with 13 patients to examine optimal planning and treatment methods. Computerized tomography (CT) scans were taken pre- and post-SOH implant. Six hypofractionated (60 Gy in 20 fractions) treatment plans were produced per patient using either a structure of rectum plus the hydrogel, termed composite rectum wall (CRW), or rectal wall (RW) as the inverse optimization structure and intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) as the treatment technique. Dose-volume histogram metrics were compared between plans to determine which optimization structure and treatment technique offered the maximum rectal dose sparing. RW structures offered a statistically significant decrease in rectal dose over CRW structures, whereas the treatment technique (IMRT vs VMAT) did not significantly affect the rectal dose. However, there was improvement seen in bladder and penile bulb dose when VMAT was used as a treatment technique over IMRT. Overall, treatment plans using the RW optimization structure offered the lowest rectal dose while VMAT treatment technique offered the lowest bladder and penile bulb dose. These treatment techniques and optimization structures have now been implemented at BC Cancer - Victoria based on this retrospective study. SOH implant has been shown not to be equally effective in all patients. Determining a priori patients in which the implant will offer most benefit allows for effective management of SOH resources. Several factors have been shown to be correlated to reduction in rectal dose including distance between rectum and planning treatment volume (PTV), volume of rectum in the PTV and change in rectum volume pre- to post-SOH. Several of these factors along with other pre-SOH CT metrics were found via multiple linear regression models to predict reduction of rectal dose using data from 21 patients who received SOH implant. Two high rectal dose metrics were modeled, change in the relative volume receiving 55 Gy and change in the partial high dose integral, integrating over the dose-volume histogram (DVH) from 55 Gy to 60 Gy. Models were also produced to predict pre-SOH RV55Gy. These models offered R-squared between 0.57 and 0.87 with statistical significance in each model. Applying a 3.5% lower limit on pre-SOH RV55Gy removed one third of patients as implant candidates. This may offer a clinically useful tool in deciding which patients should receive SOH implant given limited resources. Predictive models, nomograms and a workflow diagram were produced for clinical management of SOH implant. / Graduate

I have been intensively involved in the research on the application of currently available knowledge for the improvement of cancer care. This research covers the types of treatment that are appropriate for different clinical conditions (benchmarking and guidelines), planning services to improve access for patients, monitoring service delivery through patterns of care studies and development of the knowledge and skills of the cancer workforce. I devoted considerable effort to better educating the cancer workforce by measuring cancer teaching and developing model curricula and innovative teaching programs. I have made substantial contributions to knowledge about best practice by developing clinical practice guidelines and have developed tools and plans for cancer service delivery and have had a major influence on the training of the undergraduate and specialist medical workforce about cancer.

The main purpose of this thesis is to encourage the development of bioeffect planning as an experimental tool by which means bioeffect plans may be compared with standard isodose plans. This thesis also addresses the fundamental problems of the derivation of useful biological models for clinical application and the description of tumour and normal tissue parameter values and their variability. Particular emphasis has been placed on comparing the predictive value of the models and parameters against clinical results of fractionated and continuous irradiation either alone or combined.