The ArcCHECK dosimeter is a novel dosimetry tool that uses a helical array of silicon diode detectors to measure dose in a cylindrical plane. 3DVH is an associated software that can use ArcCHECK diode measurements along with treatment planning system (TPS) data to guide a full 3D dose reconstruction. The ArcCHECK phantom, along with 3DVH software was evaluated as a volumetric modulated arc therapy (VMAT) pretreatment verification tool. The comprehensive evaluation of the ArcCHECK and 3DVH system involved a comparison of measured dose to both ECLIPSE and Monte Carlo calculated dose for open fields and intensity modulated radiation therapy (IMRT) plans. System based confidence limits for gamma-pass rate and dose difference metrics were established through the measurement of prostate and head and neck VMAT plans. Using the system based confidence limits and clinically accepted tolerances, the sensitivity of the ArcCHECK and 3DVH system to VMAT errors was determined. Dose measured by the ArcCHECK and reconstructed in 3DVH agreed very well with dose calculated in ECLIPSE and Monte Carlo for both open fields and IMRT plans. The only results that fell outside of clinically accepted tolerances were a set of head and neck IMRT plans, however it was determined that a major factor in this result was suboptimal modelling of MLC effects in the TPS, in combination with changes in linac performance since commissioning of the TPS model. VMAT measured by the ArcCHECK and 3DVH system were in excellent agreement with ECLIPSE results and system based confidence limits were determined to be tighter than commonly used limits. ArcCHECK and 3DVH were sensitive to clinically relevant VMAT errors and insensitive to errors with little dosimetric impact, although diode measurements alone required tighter tolerances than are typically used. The ArcCHECK phantom and 3DVH software when used together have been shown to provide useful dosimetric information when used for VMAT pretreatment verification. / Graduate / 0756

Doctor of Philosophy(PhD) / The experience of persistent fatigue after breast cancer treatment is estimated to affect approximately one in four women, but fatigue development and factors associated with cancer-related fatigue are poorly understood. Gaining a better understanding of these issues is important because persistent fatigue after radiation therapy can be a debilitating experience for cancer survivors. The objectives of this study were: (1) to determine fatigue prevalence in women with breast cancer at standardised timepoints after radiation therapy; (2) to investigate the relationships between fatigue, salivary cortisol rhythm and thyroid function; (3) to investigate the amount of radiation dose received by the thyroid gland in different radiation therapy treatment techniques; and (4) to investigate the relationship between irradiation of the thyroid, thyroid function and fatigue. Participants in this research were women diagnosed with non-metastatic breast cancer and all were referred for adjuvant radiation therapy treatment. One cohort of participants (n = 48) was assessed prior to the start of radiation therapy and then six months after treatment, and a second cohort (n = 15) was assessed at six months and then at 12 months after treatment. Behavioural assessments included questionnaires that measured the level of multidimensional fatigue (MFSI–SF), the degree of fatigue and depression symptoms (SPHERE–12), impact that fatigue had on participants’ functioning (FIS) and aspects of quality of life (EORTC QLQ–C30). Biological assessments included a three day measurement of salivary cortisol rhythm and an assessment of thyroid function (TSH, free T4 and free T3). Radiation doses to the thyroid gland were determined from participants’ treatment plans. Six months after completing adjuvant radiation therapy, women receiving treatment for breast cancer experienced significant improvements in emotional fatigue, role functioning and social functioning. High fatigue levels were prevalent in 29% of women at six months and 33% of women at 12 months after treatment, but newly developed fatigue that was not present before treatment was only found in 5% of participants. There were no significant changes in cortisol rhythm over time or between fatigued and non-fatigued participants; however, significant positive correlations were found between fatigue and morning cortisol. Regarding thyroid function, significant decreases in free T4 hormone levels were seen from six months to 12 months after radiation therapy with larger decreases in free T4 levels being related to higher fatigue. Radiation doses to the thyroid gland were significantly higher in participants who received treatment to the regional lymphatics with a supraclavicular fossa radiation field compared to participants who received localised treatment to the breast or chest wall only. In the former, changes in thyroid function were observed, as were relationships between mean radiation dose to the thyroid and thyroid function.

Head and neck cancer (HNC) accounts for 3-5% of all malignancies in the United States and is the sixth most common cancer worldwide. Over the past two decades, radiation therapy (RT) has become a frequent therapeutic strategy, however one of its side effects, dysphagia has had a huge impact on patients’ quality of life. The value of determining the true prevalence of dysphagia is remarkable, which is what prompted us to carry out a study to determine the prevalence, trends, and risk factors for dysphagia following completion of RT over one year in patients diagnosed with HNC at Boston Medical Center over a 7-year period. A retrospective cohort study was conducted that involved a chart review of the medical records of all patients who completed RT for HNC cancer from January 1, 2003 to December 31, 2009 at Boston University Medical Center. 113 eligible patients were who had comprehensive treatment and follow up data at 3, 6, 9 or 12 months post RT were analyzed. Outcome variables of interest included feeding tube status, diet status, subjective swallow status, and percent weight loss from end of RT. 113 patients were identified for this study, of which 31% (n=35) were female and 69% (n=78) were male. Average age was 58.6 years old (35 to 88). The most common cancer sites were oropharynx and nasopharynx (38.9%) as well as hypopharynx and larynx (31%). 71.7% of the cohort had chemotherapy (CT) in addition to RT, and about half the patients had some degree of surgery. Altogether, the most “clinically meaningful” indicator of dysphagia (diet level of moderate/severe diet restriction) showed that the prevalence or probability of dysphagia to be 49% at 3 months, 56% at 6 months, 45% at 9 months, and 31% at 12 months. Our results suggest that about half the patients who undergo RT may be expected to develop a significant swallowing dysfunction in the first year following RT. This is extremely useful data for a health care provider to present to a patient after diagnosis of HNC and should complement counseling provided to them at the time of creating a treatment plan. Interestingly most of the patients who developed moderate/severe dysphagia did so within the first 6 months of completion of RT. Only oral cavity as cancer site was associated with moderate/severe dysphagia in our cohort of patients.

This thesis seeks to use mathematical and computational models to develop measures of clinically available data to deepen our understanding, and improve our treatments, of cancer. We consider two broad characteristics of cancer: heterogeneity, in the form of differences in cellular phenotype, and the physical microenvironment; and evolution, which has become accepted as a driver of tumour progression. To ensure that the conclusions drawn are as translatable as possible, we will attempt to use data types that are clinically available. Using a hybrid discrete-cell-based model in two spatial dimensions, we focus on these fundamental aspects of cancer, with the hope of generating new understanding and useful hypotheses to benefit current patients and oncologists. First, we model a tumour growing under the rules of the cancer stem cell hypothesis and a neutral model of evolution, and ask if we can infer the underlying biological proliferative structure. Specifically, we work toward predicting the symmetric division probability of our simulated tumours from clincally relevant observables, as this is a key driving parameter of tumour progression and therapeutic response. We focus on measures of clonal diversity, group size and shape, and a suite of statistical measures of the phylogenetic trees resulting from the tumour's evolution in different regions of parameter space. We find strikingly different patterns in these measures for changing symmetric division probability which hinge on the inclusion of spatial constraints. These results give us insight into differences between solid and liquid tumours, and also generate a number of actionable clinical and biological hypotheses. Second, we explicitly consider the physical microenvironment of tumours invading into healthy tissue, and model oxygen transport, uptake and cellular competition. We then explore the effect of spatial organisation of blood vessels within the tumour on tumour growth kinetics and cellularity. Finding wide variability in the distribution of oxygen across tumours dependent on both vascular organisation and density, we proceed to explore the utility of spatial measures of vessels on radiation efficacy. Our results offer a novel hypothesis as to the failure of vascular normalisation therapy and radiation, and a possible clinical solution.

A propriedade intelectual tem se tornado cada vez mais importante e é uma parte fundamental do desenvolvimento. No entanto, ainda é pouca literatura sobre a avaliação desses ativos intangíveis. Não se sabe ao certo sequer quais variáveis (idade, número de citações, atividade inventiva etc.), estabelecem o valor de uma patente, e essas variáveis podem diferir dependendo do setor. Também pouco se sabe sobre como se relacionam umas com as outras em termos de formação rotas tecnológicas, e quais fatores mais importantes para uma patente ser usada como inspiração para outra invenção. Neste trabalho são usadas análises de redes formadas pelas citações das patentes do segmento de equipamentos para radioterapia para descobrir o que os principais atores produziram nos últimos vinte anos no mercado de equipamentos para radioterapia. Foram levantados também os países de maior interesse de proteção dessas invenções, os principais atores no mercado. Tendências tecnológicas foram analisadas pelas formações de clusteres de reivindicações de tais documentos. Descobriu-se que a formação da rede e dos grupos de patentes têm como principal característica a semelhança das tecnologias envolvidas e, também, de fatores geográficos. Os principais playeres são grandes companhias de países desenvolvidos e praticamente não há proteção de invenções deste segmento em países emergentes ou subdesenvolvidos, com exceção da China. / Intellectual property has become increasingly important and is a key part of the development. However, it is still little literature on the valuation of these intangible assets. No one knows for sure even what variables (age, number of citations, inventive activity etc.), set the value of a patent, and these variables may differ depending on the sector. Also little is known about how they relate to each other in terms of technological routes formation, and which are the most important factors for a patent to be used as inspiration for other invention. This work analyzes the networks formed by the citations of the patents in the radiation therapy devices segment to find out what the main actors produced in the last twenty years in the radiotherapy equipment market. Countries of greatest interest to protect these inventions and the principal players were also pointed. Technological trends were identified by the formation of clusters of documents\' claims. It was found that the formation of the network and groups of patents have as main feature the likeness of the technologies involved, and also geographic factors. The main players are large companies from developed countries and there is virtually no protection for inventions in this segment in emerging or developing countries, excluding China.

Purpose: The aim of this study was to develop a method of measuring changes in the skin microcirculation and skin dose for mastectomy patients in connection with the radiation treatment. The distribution of the skin dose, its dependence on the energy of the beam, field geometry and bolus material and the accuracy of the given skin dose in the treatment planning system were studied. Finally, the correlation between the given dose and the changes in skin microcirculation was evaluated. Methods: Skin dose was measured using GafChromic EBT3 films. To evaluate the impact of different energies and field geometry measurements on a PMMA phantom were done. Dose measurements were done using an anthropomorphic phantom and in patients. The measured skin doses were compered to the doses calculated using the treatment planning system. Before and after treatment, skin blood perfusion was measured using laser speckle contrast imaging. In connection with the last measurement also methyl nicotinate was used to increase the perfusion for the measurement. Results: The measurements on the PMMA-phantom indicate that a larger photon energy results in a lower dose to the skin, but a higher exit dose. Furthermore a more oblique angle results in a higher skin dose and a larger field size also results in an increased skin dose. The patient measurements showed that the skin dose was significantly different in different areas of the irradiated field. The highest dose was measured in the area in which a bolus was applied. All patients showed a significant increase in skin blood of the perfusion within the irradiated area. The comparison between the measured doses and the doses calculated using the treatment planning system shows an underestimation of the skin dose by the treatment planning system depending on the incident angle and the presence of bolus material. Conclusion: The distribution of the skin dose during breast cancer radiotherapy in mastectomy patients is heterogeneous with the highest dose in the area of the mastectomy scar, due to the presence of bolus material. A correlation can be noticed between the changed in microcirculation and the radiation dose to the skin. Estimation of the skin dose using the treatment planning system is inaccurate, but film doseimetry offers an easy-to use method to accurately measure the dose to different areas of the irradiated skin.

Permanent breast seed implant brachytherapy (PBSI) is a recently developed form of treatment for early-stage breast cancer which can be completed in a single day procedure. Due to the reduced treatment burden, PBSI has the potential to benefit many women. However the technique has not been widely implemented, potentially related to the lack of a standardized, reproducible procedure and a high level of operator dependence. Challenges relating to target visualization uncertainties and the reliance on free-hand 2D ultrasound (US) guidance potentially inhibit adoption of the technique. This work aims to evaluate the current PBSI procedure to identify uncertainties and potential sources of errors in the current technique and develop methods to ameliorate these issues to potentially increase treatment accuracy, standardize the procedure, and reduce user-dependence. A comprehensive assessment of the current PBSI procedure was performed to identify any trends or systematic errors in the placement of seeds and establish the effects of seed placement accuracy on the treatment. Baseline seed placement accuracy, assessed in a 20 patient cohort was observed to be 9(5) mm. Random displacements of seeds from their planned position contributed significantly to the overall accuracy. No trends or systematic errors were observed across the aggregate population, however intra-patient systematic offsets were observed. The potential effects of visualization of the post-lumpectomy cavity (seroma) on treatment delivery was investigated using spatially registered CT and 3DUS images. Planning the treatment on CT, as is standard practice, resulted in less than optimal coverage to target volumes defined on US in the majority of cases. The effects of intra-operative adjustments relating to the visualization differences on the two modalities was assessed by shifting the CT-based treatment plan to centre on the US-defined seroma. Such shifts were shown to potentially contribute to the systematic displacements observed in PBSI delivery, and also had significant dosimetric effects on the planned target volumes. The impact of seroma visualization on PBSI implant accuracy was further assessed through the evaluation of CT and 3DUS images acquired for PBSI patients. Correlations were observed between the seed placement accuracy and the inter-user variability of seroma definition on CT (r = 0.74, p = 0.01) and the volume difference of the seroma on the two modalities (r = 0.65, p = 0.04), indicating that discrepancies in target delineation can impact treatment accuracy. The systematic displacements of the implants were observed to be correlated with the visualization metrics, however random displacements were independent of seroma delineation. Deviations in needle positioning during insertion may not be realized until the implant is complete, thus contributing to the random inaccuracies in seed placement. A purpose built 3DUS scanning system was investigated for its use in guiding needle insertion. Registration of the treatment template with the imaging system was validated to provide accurate target localization for needle insertion. Adjustments and re-insertion of needles under 3DUS guidance provided significant improvements to the needle positioning accuracy. A simulated implant with the guidance system indicated that overall treatment accuracy may be improved through the clinical implementation of such a system. Efforts to improve seroma definition during treatment planning and image guidance during the delivery can significantly increase seed placement accuracy and reduce the need for subjective intra-operative adjustments to the setup and needle positioning. Standardization of such advanced imaging techniques can greatly benefit the PBSI procedure by reducing user dependence and help to promote implementation. / Graduate / 2018-09-22

Background: External Beam Radiotherapy is essential in the management of locally advanced cervical cancer (LACC). Generally, VMAT is thought to achieve higher conformity to the Planned Target Volume (PTV) and better sparing of organs at risk (OAR) when compared to 3D-CRT. This study focused on these principles as it applied to treatment and potential toxicity in the management of LACC. Aim: To compare dosimetric parameters between VMAT and 3D-CRT in the management of LACC. Setting: The study analysed patients treated at Groote Schuur Hospital between May and December 2017. Method: A non-randomized comparative retrospective study. EBRT plans for 3D-CRT and VMAT were generated and data on treatment parameters for PTV D50%, Dmax, Dmean, Conformity Index (CI), Homogeneity Index, Treated Volume (TV), Irradiated Volume (IV) and OAR constraints; femoral heads, bladder, bowel bag, rectum and bone marrow were collected. Results: Of the 45 patients assessed, VMAT showed significantly lower treatment parameter values for CI (1.09 vs 1.49; p< .001) whereas, 3D-CRT showed lower Dmax (48.1Gy vs 49.2Gy; p< .001) and rectum (88.5% vs 96%). A reduced 3D-CRT dose was noted for bladder Dmax (47.4Gy vs 48.3Gy; p< .001). Conclusion: VMAT offered a superior dosimetric option, with better OAR dose sparing and optimal tumour dosimetry.

In-beam positron emission tomography (in-beam PET) is currently the only method for an in-situ monitoring of highly tumor-conformed charged hadron therapy. In such therapy, the clinical effect of deviations from treatment planning is highly minimized by implementing safety margins around the tumor and selecting proper beam portals. Nevertheless, in-beam PET is able to detect eventual, undesirable range deviations and anatomical modifications during fractionated irradiation, to verify the accuracy of the beam portal delivered and to provide the radiotherapist with an estimation of the difference in dosage if the treatment delivered differs from the planned one. In a first study within this work, a set of simulation and fully-3D reconstruction routines shows that minimizing the opening angle of a cylindrical camera is determinant for an optimum quality of the in-beam PET images. The study yields two favorite detector geometries: a closed ring or a dual-head tomograph with narrow gaps. The implementation of either detector geometry onto an isocentric, ion beam delivery (gantry) is feasible by mounting the PET scanner at the beam nozzle. The implementation of an in-beam PET scanner with the mentioned detector geometries at therapeutic sites with a fixed, horizontal beam line is also feasible. Nevertheless, knowing that previous in-beam PET research in Berkeley was abandoned due to detector activation (Bismuth Germanate, BGO), arising most probably from passive beam shaping contaminations, the proposed detector configurations had to be tested in-beam. For that, BGO was substituted with a state-of-the-art scintillator (lutetium oxyorthosilicate, LSO) and two position sensitive detectors were built. Each detector contains 32 pixels, consisting of LSO finger-like crystals coupled to avalanche photodiode arrays (APDA). In order to readout the two detectors operated in coincidence, either in standalone mode or at the GSI medical beam line, a multi-channel, zero-suppressing free, list mode data acquisition system was built.The APDA were chosen for scintillation detection instead of photomultiplier tubes (PMT) due to their higher compactness and magnetic field resistance. A magnetic field resistant detector is necessary if the in-beam PET scanner is operated close to the last beam bending magnet, due to its fringe magnetic field. This is the case at the isocentric, ion beam delivery planned for the dedicated, heavy ion hospital facility under construction in Heidelberg, Germany. In-beam imaging with the LSO/APDA detectors positioned at small target angles, both upbeam and downbeam from the target, was successful. This proves that the detectors provide a solution for the proposed next-generation, improved in-beam PET scanners. Further confirming this result are germanium-detector-based, spectroscopic gamma-ray measurements: no scintillator activation is observed in patient irradiation conditions. Although a closed ring or a dual-head tomograph with narrow gaps is expected to provide improved in-beam PET images, low count rates in in-beam PET represent a second problem to image quality. More importantly, new accelerator developments will further enhance this problem to the point of making impossible in-beam PET data taking if the present acquisition system is used. For these reasons, two random-suppression methods allowing to collect in-beam PET events even during particle extraction were tested. Image counts raised almost twofold. This proves that the methods and associated data acquisition technique provide a solution for next-generation, in-beam positron emission tomographs installed at synchrotron or cyclotron radiotherapy facilities.

Cancer is the second leading cause of death worldwide and affects millions of people every year. Furthermore, the available treatments often lead to severe side effects, thus improving radiation treatment is meaningful. Photoactivation therapy seeks to build in heavy atoms into the DNA of cancer cells, as markers, then activating them to cause secondary radiation that damages the DNA of the targeted cells only. This has been suggested but is not well understood. Hence this study seeks to investigate how a reduced model system of iodine-marked DNA is fragmented due to ionization. Computer simulations with eleven separate starting configurations of the molecule 5-iodocytidine were analyzed, for ionization levels from an average 0.03 up to 0.33 electrons removed per atom (e/N), during 200 femtoseconds (fs). A Python program was written in order to estimate bond sensitivities and identify fragments. While 5-iodocytidine resembles an iodized DNA-base it is still a rather simple model system, far from a double stranded DNA chain, and the simulations were limited to non-targeted ionization and an isolated environment. Results of this thesis include that the sugar ”backbone” of 5-iodocytidine seems to be most sensitive to ionization, fragmenting in several pieces after 150-200 fs at ionization levels of 0.30-0.33 e/N, while the rest of the molecule mostly remained intact. These results appear promising since back bone fragmentation is crucial for disrupting cancer cell growth. / Cancer är den näst största dödsorsaken i världen och påverkar miljontals människor varje år. Dessutom leder tillgängliga behandlingar ofta till allvarliga bieffekter, därför är det meningsfullt att förbättra strålbehandling. Fotoaktiveringsterapi går ut på att bygga in tunga atomer i cancercellernas DNA, som markörer, och därefter aktivera dem för att orsaka sekundär strålning vilket endast skadar de fokuserade cellerna. Detta har studerats men processerna är inte fullt klarlagda, därför ämnar denna studie att undersöka hur ett förenklat modelsystem av jod-märkt DNA fragmenteras till följd av jonisering. Datorsimuleringar för elva olika begynnelsevillkor av molekylen 5-iodocytidine analyserades, för joniseringsnivåer från ett genomsnitt 0.03 upp till 0.33 borttagna elektroner per atom (e/N), under 200 femtosekunder (fs). Ett Pythonprogram skrevs i syfte att uppskatta bindningarnas känslighet och identifiera fragment. Även om 5-iodocytidine liknar en jodiserad DNA-bas så är det fortfarande ett tämligen enkelt modelsystem, långt ifrån två sammanbunda DNA-strängar. Simuleringarna var dessutom avgränsade till icke-fokuserande jonisering och en isolerad omgivning. Resultat från den här avhandlingen innefattar att socker-”ryggraden” av 5-iodocytidine verkar vara mest känslig för jonisering, och fragmenteras i flera bitar efter 150-200 fs vid joniseringnivåer 0.30-0.33 e/N, medan resten av molekylen oftast förblir intakt. Dessa resultat ser lovande ut eftersom fragmentering av ryggraden är särskilt viktig för att hämma tillväxten av cancerceller.