RapidArc (Volumetric Modulated Arc Therapy) is an advanced radiotherapy technique which can achieve excellent target volume coverage and organ at risk (OAR) sparing. The potential role of RapidArc in the treatment of head and neck cancer (HNC) was evaluated by planning studies comparing RapidArc with fixed gantry IMRT, and a prospective study to assess clinical outcomes in patients treated with RapidArc. In the planning study evaluating oropharyngeal tumours, RapidArc achieved comparable dose distributions to IMRT with significantly improved dose conformity and reduced monitor units {M Us). However, in the study evaluating nasopharyngeal and paranasal sinus tumours, target volume coverage and sparing of some OARs were marginally inferior with RapidArc. Preliminary results have indicated that toxicity is acceptable in patients treated" with RapidArc and comparable to fixed gantry IMRT.

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Despite the advances in diagnostic and therapeutic techniques, the outcome and survival of patients suffering from head and neck cancer has remained poor, primarily due to late detection, and the tendency of the disease to develop loco-regional metastasis. A key to its control is early detection and treatment and prevention of recurrence and metastasis. Tumour metastases can be considered as complex multi-step molecular events which involve the interplay between several processes including changes in cell survival, adhesion, proteolysis, and angiogenesis. Based on these considerations, a positive correlation between tumour invasiveness and expression/suppression of these processes would be expected. Photodynamic Therapy (PDT) is a novel treatment modality for a variety of malignant tumours, including head and neck cancer. The technique is based on the combination of a photosensitive drug and visible light to disrupt cell function and induce cytotoxicity, but there is little agreement on its efficacy. Furthermore, PDT is indicated for early tumour without metastases, yet it is crucial to determine its influence on the metastasis process. The aims of the study were: (i) to explore, using an in vitro model, the influence of PDT, alone or in combination with either chemotherapy or small molecules, on cell toxicity, expression of α5β1 and αvβ6 integrins and epidermal growth factor receptor (EGFR), production of matrix metalloproteinases, MMP-2, MMP-9 and MMP-13, urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF); (ii) to clinically evaluate the potential of PDT as a tool for head and neck cancer treatment; (iii) to clinically evaluate the ability of an optical system, based on fluorescence and elastic scattering spectroscopy, to distinguish between normal, potentially malignant and malignant tissues and to develop an applicable algorithm that can be used as a standard for the subsequent analysis of "unknown" lesions; (iv) to monitor the sensitiser photobleaching during PDT in patients with superficial basal cell carcinoma (BCC), and compare this to clinical outcome. It was found that, using a series of human oral squamous cell carcinoma cell lines, a marked decrease of tumour invasion and migration is evident after PDT this was associated with the downregulation of MMP-9, -2 and -13, uPA and VEGF. Moreover, this migratory inhibition was further enhanced when PDT was combined with either cisplatin chemotherapy or tyrosine kinase inhibitors. Clinically, a complete response with excellent cosmetic results was achieved on patients treated with PDT. Both fluorescence and elastic scattering spectroscopy have shown a great potential to both non-invasively identify dysplastic changes at an early stage and to be used as a screening tool for the detection of subsequent primary lesions. This thesis has demonstrated that, PDT and its related optical system together are able to detect, treat and reduce invasion and metastasis of head and neck carcinoma.

Image Guided Intensity Modulated Radiotherapy (IG-IMRT) incorporates novel imaging strategies into IMRT planning and delivery. FDG-PET/CT imaging may be used to identify potentially radioresistant tumour cell populations in head and neck cancer (HNC). Dose-painting with IMRT is a novel technique which provides an opportunity to widen the therapeutic window by dose escalation to radioresistant subvolumes. The purpose of this thesis was to evaluate the feasibility of th is technique, to provide methodology for identification of the FDG-avid region and to inform on a reasonable dose level to use in a future phase I clinical study investigating dose-painting to the FDG-avid target volume. This technique requires confidence in the quality of geometric and dosimetric accuracy of delivery and this issue was investigated in this thesis. Pre-clinical work included a comparison of five different FDG segmentation techniques. One of these techniques was used to identify the FOG-avid biological volume selected to receive dose-painting with IMRT in a planning study. Four dose levels were tested. Radiobiological modelling was used to determine an optimal dose level as the basis for a future clinical study and to determine the impact of using different FDG segmentation techniques. A clinical study was performed in patients with HNC to compare in -room volumetric imaging - cone beam computed tomography (CBCT) - with planar kilovoltage (kV) electronic portal imaging (EPI) for aspects of image guidance and to inform on appropriate planning margins. Pre-clinical work suggested that dose-painting with IMRT to the FOG-avid subvolume would be associated with increases in estimated tumour control probability (TCP) and with acceptable increases in normal tissue complication probability (NTCP). Verification using CBCT provided accurate data to guide treatment delivery and appropriate planning margins. The findings reported in this thesis provide valuable information that will inform the design of future clinical studies.

Radiotherapy is commonly used in the treatment of head and neck cancer. For early stage tumours, conventional radiotherapy techniques have a high cure rate and low levels of long-term complications. Patients with more advanced cancers have much lower cure rates and high levels of treatment-related complications. Intensity modulated radiotherapy (IMRT) is a new form of focussed radiation therapy. It has been used to reduce the radiation dose to normal tissue structures and increase the dose delivered to tumour bearing tissues. This potentially allows reduced side effects and increased tumour control compared to conventional radiotherapy. The rationale of this thesis was to test whether these twin goals could be achieved in head and neck cancer patients. The first part of the thesis describes improvements in patient immobilisation, optimisation of techniques for neck irradiation, and evaluation of the technique in a busy radiotherapy department. It includes pre-clinical evaluation of IMRT for different tumour sites, the development of quality assurance programs and the conduct of a national randomised controlled trial of parotid-sparing IMRT. This trial concluded that IMRT significantly reduced patient-reported xerostomia, allowed recovery of saliva production and improved quality of life. The second part of the thesis describes pre-clinical evaluation of techniques to escalate radiation dose in patients with larynx and hypopharynx tumours. A phase I/II clinical trial showed that higher doses of radiation can be delivered at the expense of an increase in acute radiation toxicity but without a measurable increase in late radiation side effects. In the larynx and hypopharynx groups, a possible increase in local control was observed. This thesis describes the process of evaluation of a new radiotherapy technology and could be used as a template for testing other new technologies in the future.

This thesis considers whether the alteration of telomere function by manipulation of the telomerase enzyme can affect the radiosensitivity of in vivo derived SCCHN cells and hence whether telomere dysfunction inducing strategies are likely to be synergistic with ionising radiation in the management of SCCHN. The role of telomerase in radioprotecting cancer cells is investigated using the ectopic expression of hTERT in cell lines with high and low levels of telomerase. The effect of inhibiting telomerase expression is examined using a dominant negative telomerase gene. This approach had little success in SCCHN cells and so further experiments designed to elaborate the effect of telomerase inhibition on radiosensitivity were carried out using the small molecule reverse transcriptase inhibitor 3’ – azido, 3’ – deoxythymidine (AZT). These showed both telomerase suppression and increased radiosensitivity in cells exposed to AZT in culture. Other suggested factors which may affect the success of radiotherapy for cancer include the missense mutation of the p53 gene. A common polymorphism at codon 72 gives rise to Arginine or proline forms of the protein. This thesis investigates whether this variation affects radiosensitivity in SCCHN cells by assessing a panel of in vivo derived SCCHN cell lines. If the level of telomerase expression does not impact on radiosensitivity, then the use of antitelomerase strategies may be less effective with higher levels of telomerase expression in tumours. Continued selective pressure during tumour progression may mean the emergence of clonal variants with improved telomere function via greater levels of telomerase. This is investigated by anaphase bridge scoring of primary and recurrent archival tumour material. Analysis of cells from primary lesions and then from recurrent disease in the same patient provides information in this regard.