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The EPID (electronic portal imaging device) was designed for in vivo imaging of patients during radiotherapy treatment. The ability of EPIDs to promptly acquire two dimensional data, lends them to be considered for use in quality assurance of the linac. This thesis set out to investigate the possibility of using a radionuclide, technetium 99 m (Tc99m), to produce a flood field for the calibration of an EPID, because using a beam calibrated EPID to measure the beam is self-referential. The difference in relative response between the energy spectrum of a 6MV beam and the Tc99m was investigated using EGSNRC DoseXYZ Monte Carlo Modelling. The relative output ratio was calculated to be less than 1.6%. The dose response of the EPID with respect to dose rate was checked using different activities of Tc99m and found to be linear. The flatness from a phantom was calculated, with a model in MATLAB, for a range of heights, overlaps, thickness, and deformations, to find the optimum balances between signal strength and flatness. This model was checked for accuracy using diagnostic radiographic film. The culmination of the energy response, linearity and the calculated flatness is a flood field taken with a flood phantom on the EPID with low signal strength. To get a signal to noise ratio of 3% the mean of over 2000 flood field images were used. This accuracy was not adequate for clinical use but the averaging of pixels it is accurate enough for QA.

A Varian 4 MeV isocentric therapy accelerator has been modified to perform also as a CT scanner. The goal is to provide low cost computed tomography capability for use in radiotherapy. The system will have three principal uses. These are (i) to provide 2- and 3-dimensional maps of electron density distribution for CT assisted therapy planning, (ii) to aid in patient set up by providing sectional views of the treatment volume and high contrast scout-mode verification images and (iii) to provide a means for periodically checking the patients anatomical conformation against what was used to generate the original therapy plan. The treatment machine was modified by mounting an array of detectors on a frame bolted to the counter weight end of the gantry in such a manner as to define a 'third generation' CT Scanner geometry. The data gathering is controlled by a Z-80 based microcomputer system which transfers the x-ray transmission data to a general purpose PDP 11/34 for processing. There a series of calibration processes and a logarithmic conversion are performed to get projection data. After reordering the projection data to an equivalent parallel beam sinogram format a convolution algorithm is employed to construct the image from the equivalent parallel projection data. Results of phantom studies have shown a spatial resolution of 2.6 mm and an electron density discrimination of less than 1% which are sufficiently good for accurate therapy planning. Results also show that the system is linear to within the precision of our measurement (≈ .75%) over a wide range of electron densities corresponding to those found in body tissues. Animal and human images are also presented to demonstrate that the system's imaging capability is sufficient to allow the necessary visualization of anatomy.

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Tumour hypoxia has been demonstrated to cause development of an aggressive tumour phenotype and is associated with increased patient mortality and poorer response to treatments such as chemotherapy and radiotherapy. Previous studies have established that hypoxia exists within a nidus of prostate cancer. Based on the importance of the tumour microenvironment, especially hypoxia, in prostate cancer, the major aims of this thesis were to establish: (a) the role of a novel putative survival factor, dermcidin, in prostate cancer survival under hypoxia/oxidative stress; and (b) the effect of nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDS), a new class of drugs, on the killing of prostate cancer cells subjected to hypoxia. A wide-range of confirmatory, cellular and molecular biology techniques were employed in this thesis. The PC-3 hormone-insensitive prostate cancer cell line was used for the majority of studies as this cell line represents hormone-independent prostate cancer, treatment of which is currently palliative. Cell incubation at 0.2% oxygen for 48 hours was established as suitable conditions to stimulate the development of the hypoxia response. Upregulation of nuclear hypoxia-inducible factor-1α protein was the main marker used to assess the hypoxia response. Dermcidin messenger RNA production was found to occur in a range of prostate cancer cell lines; was upregulated in cell lines by both hypoxic and oxidative stress; and found to act as a proliferation, survival and pro-invasion factor under hypoxia and oxidative stress in immortalised prostate cancer cell lines. Furthermore, the portion of the dermcidin molecule responsible for the survival advantage was localised to the proteolysis-inducing factor core peptide subunit. However, subsequent analysis of primary cancer samples from prostate cancer patients revealed that dermcidin was not expressed in these tumours, although dermcidin mRNA was identified in analysis of other primary tumours. As such, the role of dermcidin in prostate cancer was not evaluated further in this thesis. Investigation of NO-sulindac (a NO-NSAID drug) in hypoxic PC-3 cells showed that these agents were significantly more pro-necrotic, pro-apoptotic and anti-invasive than traditional, unnitrated sulindac. NO-sulindac was found to downregulate the hypoxia response mounted by PC-3 cells under hypoxia via the Akt signalling pathway. Finally, analysis of the role of NO-sulindac in radiosensitising hypoxic PC-3 cells showed that NO-sulindac caused significant radiosensitisation under normoxia, but particularly in hypoxic conditions. As such, NO-NSAIDs show great promise as neoadjuvant, concurrent and adjuvant treatments for patients with hypoxic prostate cancer. The findings of this thesis illustrate several potential novel strategies for treatment of hormone-independent prostate cancer.

Background In the treatment of head and neck cancers (HNCs), radiotherapy (RT) has the advantage of organ preservation compared to surgery. However, treatment toxicities associated with RT can affect important functions for everyday life, both in the acute and late stage. RT to macroscopic tumour in HNC is commonly combined with elective RT to cervical lymph nodes at risk of microscopic involvement. The resulting risk reduction of the elective treatment based on dose-volume parameters is sparsely evaluated. So is the relationship between the elective treatment and treatment toxicity. The present thesis addresses these aspects. A strategy aimed at improving the outcome of RT is accelerated fractionation (AF). AF strives to shorten total treatment time to minimise proliferation of the tumour tissue during the RT period. We have investigated the impact of AF on both disease control and toxicity. Methods In the ARTSCAN study, 750 patients with localised HNC were randomised between AF (68 Gy in 4.5 weeks) and conventional fractionation (CF) (68 Gy in 7 weeks). The elective treatment volume was prescribed 46 Gy with CF in both treatment arms. The thesis is based on four individual papers, investigating the issues above in the whole study population or in sub-populations. Results No difference in disease control or late toxicity between CF and AF was observed at five years. However, there was an increased acute toxicity with AF. Weight loss was associated with treatment volume, independent of tumour stage. The elective treatment volume was found to be an independent risk factor for late aspiration, as well as mean dose to the pharyngeal constrictor muscles, neck dissection, and age at randomisation. There was a significant risk reduction for node relapses in volumes treated to an elective dose. Only a relapse in volumes treated to >60 Gy affected the survival. Conclusion The present thesis questions the benefit of AF in definitive RT as well as extensive elective treatment of the cervical nodes.

The main subject matter of this thesis concerns radiotherapy patient scheduling subproblems formulated as four separate shop scheduling problem models (i.e. hybrid flowshop, flowshop, mixed shop and multiple identical parallel machine scheduling problems) based on the characteristics of the intricate real-life treatment processes observed at the Arden Cancer Centre in Coventry, UK. Insight into these processes was gained by developing and using a novel discrete-event simulation (DES) model of the four units of the radiotherapy department. By typifying the subproblems as well-known scheduling problem models, it was intended that methods amenable to them such as heuristics be used in the study. Four novel constructive heuristics based on priority dispatching rules and strategies adapted from some established algorithms have been developed and implemented using the C++ programming language. Further, these heuristics were incorporated into the DES model to create schedules of appointments for the patients generated daily. The effectiveness and efficiency of the constructive heuristics have been tested using the following performance criteria: minimising i) average waiting time to the start of treatment, and ii) average percentage of patients late for their treatment, and iii) the amount of overtime slots used for the patients received in a given period of time. The coordinated constructive heuristics and the DES model have also been tested using possible alternative pathways patients can follow in the treatment unit. The aim of these tests was to compare the efficiency of the radiotherapy department’s current pathway to other possible pathways. Further, strategies for using maximum allowed breaches of targeted due dates, reserved slots for critical treatments and overtime slots was also included in the heuristics. The results of several tests showed that the heuristics created schedules of appointments whose average waiting times for emergency, palliative and radical treatments improved by about 50%, 34% and 41%, respectively, compared to the historical data. However, their major slack was evidenced by the fact that about 13% of the patients needing palliative treatment were expected to be late for treatment compared to about 1% of those requiring radical treatment.