Laboratory studies have demonstrated that some radioresistant tumours are hypersensitive to low doses of radiotherapy (< 1Gy) and characteristically display features of radioresistance at more conventional radiation doses (2Gy per fraction), i.e. there is excess cell kill at doses < 1Gy relative to that predicted by the linear quadratic (LQ) model. This phenomenon is called "low dose hyper-radiosensitivity" (LDHRS). The aim of this thesis was to investigate if LDHRS could be demonstrated in tumours and in normal tissues and to assess whether there was a difference between them that could be exploited clinically. The epidermal basal cell layer of human skin was chosen as a model of normal tissue. 8 patients with metastatic tumour nodules to skin were recruited. The nodules were measured, their volume calculated and randomised to receive conventionally fractionated radiotherapy (1.5Gy/day) or ultrafractionated radiotherapy (0.5Gy TDS with a 4hr inter-fraction gap). Both groups were treated for 12 days. Measurements were taken on days 0, 5,8,12 & 26 and monthly until regrowth occurred. Time to regrowth to original volume was calculated and compared between groups using the Wilcoxon Signed Rank test. In addition skin biopsies were performed on days 0, 5, 8, 12 and 26 changes in BCD were compared using non-linear regression analysis. Proliferation was assessed using the proliferation markers Ki67 and Cyclin A. Analysis of all re-growth data demonstrates greater tumour growth delay in the nodules treated with the "ultrafractionated" regime. This was most marked in tumours generally accepted as being radioresistant and known to show LDHRS in vitro, 2-tailed p-value 0.009. Analysis of the surrounding normal skin does not demonstrate any evidence of LDHRS The proliferative response was similar in both treatment groups. In-vitro experiments carried out in parallel failed to demonstrate LDHRS following multiple low doses of radiation in Hs633T - a sarcoma cell line that has demonstrated LDHRS to single low doses. It was concluded that there was a potential therapeutic window that could be exploited by using "ultrafractionated" radiotherapy for the treatment of "radioresistant" tumours". A feasibility study of "ultrafractionated" radiation in high-grade glioma (HGG) was initiated, with the ultimate aim of a larger phase II study. To date 2 patients have been recruited to the feasibility study.

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Despite its benefits in cancer treatment, ionising radiation (IR) can induce a series of adverse acute and/or long term effects. Studies on A-bomb survivors and radiotherapy patients have shown that acute whole-body exposure results in an increased risk for radiation-induced Acute Myeloid Leukaemia (r-AML), a bone marrow (BM) malignancy; whereas local-radiotherapy patients run the risk of developing acute and/or long term normal tissue reactions. Irradiated BM cells manifest persistent radiation-induced genomic instability. BM is one of the most susceptible tissues to radiation-induced cancer and one of the most radiosensitive tissues, which proposes a link between cancer susceptibility, genomic instability and radiosensitivity. The exact mechanism by which exposure of BM cells to IR leads to malignant transformation is still unclear, but the non-targeted nature of radiation-induced damage and genomic instability could suggest that an epigenetic mechanism is also involved; and DNA methylation is a good candidate. This thesis investigated genetic and epigenetic factors that may be involved in biological responses to ionising radiation exposure. Stem cell frequency is genetically determined in mouse haemopoiesis and is possibly part of the equation that defines cancer risk. Global DNA methylation levels were assessed in control haemopoietic tissues and radiation-induced leukaemias. The methylation status of haemopoietic malignancies reflects that of their untransformed tissue. Additionally, DNA methylation levels of untransformed haemopoietic tissues were found to correlate with their relative radiosensitivity in vivo. In vivo responses to ionising radiation were found to be under the influence of both genetic and epigenetic factors, highlighting the complexity of such biological reactions.

Background: Movement of tumours between or during radiotherapy treatment fractions poses a risk to surrounding healthy tissues and potentially lowers the treatment dose to the intended area. To increase the efficacy of radiotherapy, radiation oncologists utilise image-guided radiotherapy (IGRT) to enhance the delivery of radiation to cancerous tumours. Concern about concomitant radiation doses and poor quality images have previously limited the use of such technology when developing treatment plans for adaptive radiotherapy. Recent improvements to the On-board Imager (OBI; Varian version 1.4) including expansion of the number of acquiring modes from four to six, have rejuvenated efforts to use Cone Beam Computed Tomography (CBCT) with OBI as a radiotherapy treatment planning tool. Aim: This research aimed to investigate the possibility of using the new version of the Varian On-Board CBCT imager Vl.4, for adaptive radiotherapy. This work has led to the development of a methodology on how to initiate and implement CBCT scans for - - - - - -- -. -- - -- .- -- the purpose of increasing the accuracy of radiotherapy treatments using adaptive radiotherapy. Methods: The adaptation of radiotherapy plans using CBCT scan images involved three stages. CBCT concommitant doses were determined in the first stage by measuring the dose received by three types of phantom; the RANDO anthropomorphic phantom, the computer-imaging reference system phantom (CIRS) and cylindrical water phantoms of varying diameter. Two- and three-dimensional simulations were also obtained for CBCT using EXCEL, and Monte Carlo codes (BEAMnrc and DOSXYZnrc). The manufacturer's schematic diagram of the head was used to simulate a detailed CBCT dose simulation with the effect of beam output and bow-tie filter included as dose-modifiers. Based on these dose measurements, relationships between CBCT concomitant dose and patient size were found. In addition, estimations of secondary induced cancer were modelled based on these doses. In the second stage, CBCT scan calibrations were conducted. The relationship IV Abstract between the Hounsfield Unit (HU) and electron density (ED) of CBCT scans were described mathematically for each CIRS-062A phantom configuration. Later, these CBCT HU-to-ED calibrations were benchmarked against the CT RU-to-ED relationship of GE lightspeed CT employed in treatment planning. Finally, in the third stage, the obtained HU-to-ED calibrations were applied to treatment plans calculated on CIRS and RANDO phantoms using single-beam and IMRT configurations. Dose calculations derived from the OBI CBCT were compared with those from the GE Lightspeed CT. Results:Using a female RANDO phantom, doses were lowered by factors of36, 8,22 and 16, at the eyes, oesophagus, thyroid and brain, respectively, when using the new version ofVarian CBCT vl.4. In both the standard dose head mode and pelvis mode, the concomitant dose at all positions decreases as the phantom size increases. The concomitant dose measured on the smallest cylindrical water phantoms (10cm in diameter) resulted in a theoretical risk of secondary skin cancer of 0.005% in the standard dose mode and 0.05% in the pelvis mode, assuming a 30-fraction course of ---- -treatmentwith CBCT images acquired on a daily basis. Importantly, these-doses are - approximately 10 times greater than those measured for the largest phantom. The risk of secondary cancer for this phantom size at the oesophagus, thyroid, and brain sites are 0.0443, 0.0106 and 0.0439 % respectively for 30 daily images of head and neck treatment. Dose calculations on both the CIRS and RANDO phantoms showed that for the single beam treatment, only 1 % difference in the mean dose values are delivered to the majority of insertions when using the original CT or CBCT images and respective calibration curves. The only exception was for dense bone, which exhibited a 2% difference. For the IMRT treatment plan results showed that when the CT scan image is used the mean doses were less than 1.1 %. Conclusion: CBCT doses from the OBI version 1.4 are significantly lower than doses from version 1.3, making it possible to use CBCT to assist with adaptive radiotherapy on a daily basis, without a significantly increased secondary cancer risk. This technology is a useful tool to aid patient positioning for radiotherapy and to allow v Abstract VI daily adaptive IGRT. Radiation dose varies significantly with both patient size and tumour position in relation to scanning mode. It is therefore recommended that patient-specific imaging protocols be considered, especially with regard to paediatric patients who can be expected to receive a higher dose. The single beam and the WRT comparisons showed that the CBCT images and calibration curves can be used in treatment planning.

Pelvic radiotherapy creates both physical effects and psychological responses that negatively affect the sexual health of women and their partners. However, the clinical assessment and management of female sexual difficulties does not receive equivalent professional focus as that of male sexual dysfunction after cancer treatment. The overall aim of this study was to explore the factors that influence the clinical assessment of treatment-induced female sexual difficulties within routine medical follow-up. The purpose of this exploration was to identify the key components of a clinical assessment methodology that could be developed to improve the evaluation of psychosexual morbidity associated with radiotherapy for women with pelvic malignancy.

40% of all patients cured of cancer receive radiation therapy as a part of their treatment. However, acquired or intrinsic resistance remains a major obstacle in increasing this already effective treatment, particularly in the treatment of NSCLC. Therefore, new approaches are needed to increase its biological effectiveness. A major pathway of tumour radiation resistance is through inactivation of cell death pathways. Our aims were to develop and characterize an in vitro model system of NSCLC radiation resistance following fractionated exposures that mimic clinical treatment regimes, as well as, to manipulate the apoptotic and autophagic death pathways as a means to sensitize NSCLC to radiotherapy. We found that exposure to a series of fractionated treatments resulted in acquired resistance of NSCLC cell lines to IR. In addition, we found that cisplatin-resistant NSCLC lines, developed following similar fractionated exposures, were also radiation-resistant. Our results suggest that there may be common pathways of radiation/cisplatin-resistance, and by studying modes of cell death, we can target under-utilized cell death pathways to improve the efficacy of radiation treatment. We modulated apoptosis induction by inhibiting caspases (Z-VAD-fmk) and BcI-2 anti-apoptotic proteins (Obatoclax). Our results showed that apoptosis plays a minor role in radiation-induced cell death. While caspase and BcI-2 anti-apoptotic protein inhibition resulted in changes in apoptosis, we observed no change in clonogenic survival. We then targeted autophagy induction through the inhibition of mTOR by Rad001. We found that mTOR inhibition resulted in decreased autophagy, suggesting that autophagy was being utilized as a survival mechanism in NSCLC, thus causing a significant reduction in cell survival following IR treatment. However, in combination with IR, both Obatoclax and Rad001 did not cause an additive or synergistic increase in cell death. Cell cycle analyses revealed that alternative mechanisms of cell death such as mitotic catastrophe and senescence may play a more pivotal role in IR-induced cell death. Altogether, our studies reveal that NSCLC cells may undergo multiple cell death pathways in response to IR. Our fractionated model system, as a mimic of clinical acquired radiation-resistance, will facilitate further examination of the mechanisms of radiation resistance. And our findings suggest that manipulation of alternative death pathways (such as mitotic catastrophe and senescence) in NSCLC needs further examination as a target for tumour sensitization to radiotherapy.

The primary aim of radiotherapy is to deliver sufficient doses in order to eradicate a tumour whilst sparing damage to normal tissue. Advanced radiotherapy techniques such as Intensity modulated radiation therapy (IMRT) have been developed that aspire to improve the conformity of beam delivery in order to improve tumour control and reduce normal tissue complications. It is of vital importance to determine the response to modulated fields within the directly targeted and out-of-field regions and to gain greater understanding of the mechanisms driving the response, This work investigates the cell survival and DNA damage responses following modulated radiation field delivery. It has shown that significant decreases in cell survival occur within regions outside the radiation field following the delivery of modulated radiation. It has demonstrated for the first time the spatial and temporal characteristics of DNA damage and repair across a modulated radiation fie ld. Initial and residual DNA damage was shown to increase within out-of-field regions following modulated radiation field delivery. The bystander effects were observed to occur independently of several parameters such as dose-rate, hypoxia and dose fractionation. It can be concluded that intercellular communication between populations ill- and out-of-field is pivotal for the induction of out-of-field cellular responses that may need to be considered further as potential effectors of clinical outcome.

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