External beam radiation therapy (EBRT) is the most common form of radiation therapy (RT) that uses controlled energy sources to eradicate a predefined tumour volume, known as the planning target volume (PTV), whilst at the same time attempting to minimise the dose delivered to the surrounding healthy tissues. Tumours in the thoracic and abdomen regions are susceptible to motion caused mainly by the patient respiration and movement that may occur during the treatment preparation and delivery. Usually, an adaptive approach termed adaptive radiation therapy (ART), which involves feedback from imaging devices to detect organ/surrogate motion, is considered. The feasibility of such techniques is subject to two main problems. First, the exact position of the tumour has to be estimated/detected in real-time and second, the delay that can arise from the tumour position acquisition and the motion tracking compensation. The research work described in this thesis is part of the European project entitled ‘Methods and advanced equipment for simulation and treatment in radiation oncology’ (MAESTRO), see Appendix A. The thesis presents both theoretical and experimental work to model and predict the respiratory surrogate motion. Based on a widely investigated clinical internal and external respiratory surrogate motion data, two new approaches to model respiratory surrogate motion were developed. The first considers the lung as a bilinear model that replicates the motion in response to a virtual input signal that can be seen as a signal generated by the nervous system. This model and a statistical model of the respiratory period and duty cycle were used to generate a set of realistic respiratory data of varying difficulties. The aim of the latter was to overcome the lack of test data for a researcher to evaluate their algorithms. The second approach was based on an online polynomial function that was found to adequately replicate the breathing cycles of regular and irregular data, using the same number of parameters as a benchmark sinusoidal model.

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The purpose of the present thesis was to better understand the effect of targeting key biological mechanisms in order to improve radiotherapy response. Two important and distinct pathways were targeted using novel agents: (1) the phosphoinoside-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway; (2) the ataxia telangiectasia-mutated-Rad3-related (ATR)/Chkl pathway. The role of the PI3K1mTOR signalling pathway in tumour radiosensitivity and tumour microerivlronment (TME) was examined using three, recently-developed signalling inhibitors obtained from Novartis Pharma: NVP-BEZ235 (dual PI3K1mTOR inhibitor), NVP-BGT226 (dual PI3K1mTOR inhibitor) and NVP-BKM120 (single PI3K inhibitor). The radiosensitising potential of NVP-BEZ235 and NVP-BGT226 was demonstrated in tumour and endothelial cells. Additionally, a thorough research into the effects ofNVP-BKM120 and NVP-BEZ235 on TME showed that oncogenic signalling inhibitors can improve vascular morphology and increase tumour oxygenation and perfusion in tumour xenograft models, resulting in improved radiation response. Furthermore, a highly potent and selective A TR inhibitor, VE-822, that was obtained from Vertex Pharmaceuticals (Europe) Ltd, was tested in pancreatic ductal adenocarcinoma (PDAC) cells and tumour xenograft models. A TR inhibition by VE-822 resulted in sensitisation of tumour cells but not normal cells to radiation and gemcitabine. Similarly, VE-822 strongly enhanced radiation- and chemoradiation-induced tumour growth delay in tumour xenograft models. Importantly, VE-822 did not potentiate radiation-induced gastrointestinal tract epithelial damage. To summarize, the impact of targeting two distinct pathways in combination with radiation and chemoradiation was explored. Inhibition of the PI3K1mTOR and ATRlChkl signalling pathways increases response of tumours to radiotherapy they and might be promising targeting strategies for cancer treatment. Our findings have considerable translational implications and future clinical trials should aim to validate these observations.

Gnathic changes after head and neck radiotherapy have not been thoroughly characterized radiographically. The objectives of this study are to characterize changes to the teeth and jaws on panoramic images following intensity modulated radiotherapy (IMRT), and to determine whether subject comorbidities and radiation dose affect these changes. This retrospective analysis reviews the charts and panoramic images of 126 head and neck cancer patients who received IMRT at Princess Margaret Hospital between January 1, 2005 and December 31, 2008. Of the 126 subjects, 75 (60%) showed changes on panoramic radiographs; 66 (88%) of which consisted of widened periodontal ligament spaces (WPLS). The median time to WPLS was 29 months after IMRT. Female sex and dose correlated with decreased time to WPLS. These results suggest that WPLS is a common radiographic sign following IMRT that may not require endodontic intervention as post-IMRT WPLS is unrelated to the pulpal status of the tooth.