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There have been developments in radiation therapy treatment techniques, which lead to an increase in the complexity of these treatments. The aim is to deliver highly conformal three-dimensional (3D) dose distributions, such as stereotactic radiosurgery (SRS). Polymer gel dosimetry offers three-dimensional (3D) dosimetry techniques for dose verification of dose distributions. N-isopropyl-acrylamide (NIPAM) polymer gel was the latest to develop and can be prepared under a normal atmospheric environment and has lower toxicity compared with the highly toxic polymer gels used earlier. NIPAM polymer gel using X-ray computed tomography (CT) was experimentally investigated in terms of its X-ray CT dose response, sensitivity and dose resolution. The effect of radiation beam type, radiation beam energy and radiation beam dose rate on X-ray CT dose response have also been studied. The temporal stability of NIP AM polymer gel has been examined over several days post-irradiation. The change in the polymer gel dosimeter’s physical and electron densities as a function of absorbed dose was also investigated. In this study two new prototype phantoms were designed and constructed for imaging and irradiation of polymer gel dosimeters to provide simplicity and practicality for clinical dosimetry. The dosimetric and water equivalence properties of four NIP AM based polymer gel dosimeter formulations have been studied by examining their physical properties, interaction probability, radiation transport parameters and performing Monte Carlo modelling of depth doses. NIPAM polymer gel dosimeter irradiated at different doses using 6 MeV photon beam and 400 MU min-1 dose rate were found to have higher CT dose response (up to 37. 8% at 10 Gy dose point) than results reported in the literature for NIP AM gel using similar concentration. The CT dose sensitivity of NIP AM polymer gel was found to be 0. 405+-0. 014 H Gy-1, which is 26. 2% higher than the reported sensitivity of 0. 321+-0. 008 H Gy-1 with similar NIP AM gel concentration. The maximum change in physical density as a function of absorbed dose for polymer gel dosimeters was found to be up to ~1. 0% for an absorbed dose of 20 Gy. The variations observed in the CT dose response curves for NIP AM gel dosimeters irradiated at different radiation dose rates were small. Therefore, NIP AM polymer gel dosimeters were found to be insensitive to variation in radiation beam dose rate for a 6 MeV photon beam. NIP AM polymer gel dosimeters showed very good temporal stability at different post-irradiation imaging times up to 14 days. The variations of NIP AM polymer gel dosimeters CT dose response were within experimental uncertainty for all dose rates and imaging times studied. Due to its low concentration NIP AM polymer gel had lower dose resolution of -1. 54 Gy compared with -0. 052 Gy for the highest NIP AM concentration published in the literature. The MDD was found to be -2. 5 Gy. NIPAM3% polymer gel formulation (the lowest concentration) had the most dosimetric and water equivalence properties over the energy range investigated. NIPAM15% had the least water equivalent properties due to its higher monomer concentration. NIPAM3% was found to be more water equivalent than other X-ray CT polymer gel dosimeters. In summary, X-ray CT polymer gel dosimetry is a low contrast and low sensitivity (and hence low dose resolution) technique due the fact that only small density changes occur within the irradiated polymer gel dosimeter. This has been the limiting factor of X-ray CT polymer gel dosimetry from gaining widespread acceptance for clinical dosimetry. Observations have shown that careful handling should be applied when transporting polymer gel dosimeters because of their sensitivity to movement shocks, when they may lose their gelling matrix integrity. Hence, it is recommended to establish polymer gel dosimetry as an in-house dosimetry technique, where full polymer gel dosimetry procedures can be performed on-site within the clinical facilities to eliminate errors.

Over the last few decades, radiation therapy techniques have been greatly improved, with more complex radiation delivery systems such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) being used to treat complex tumour shapes. This has greatly increased the demand for more accurate dosimetry systems to achieve better targeting of the treatment area while sparing the surrounding normal tissues. Ge-doped SiO2 telecommunication optical fibres are a potential form of thermoluminescence (TL) dosimeter that offers excellent TL yield as well as high spatial resolution, the size of the optical fibre (typically ≈100 μm) making it particularly suitable for use in a variety of interface dosimetry situations and also for small radiotherapy fields. Using the Ge-doped SiO2 optical fibres as a dosimeter, the work in this thesis aims to present measurement of the dose enhancement that can be obtained close to high atomic number media. For present purposes iodine and gold have been investigated as generators of photoelectrons using 250 kVp photons produced by a Gulmay orthovoltage x-ray machine. Additional investigation is made of the dosimetry of small photon field sizes ≤ 4 x 4 cm for 6 MV energy produced by a Varian linear accelerator. Results are presented for Ge-doped SiO2 telecommunication optical fibres with different core diameters. These have first been characterised in terms of linearity, energy dependence and glow curve, good linearity to dose being obtained, the fibre with a 50 pm core dopant diameter providing the greatest TL yield. Consequently, it was used for dose enhancement investigation with iodine and different thicknesses of gold coated to the fibre i.e. 20, 40, 60, 80, and 100 nm thickness. The experimental results were favourably compared against Monte Carlo simulations with FLUKA and DOSRZnrc. The 50 μm core dopant diameter Ge-doped SiO2 optical fibres were also used for dosimetric study of field sizes of 1.0 cm x 1.0 cm, 2. 0 cm x 2.0 cm, 3.0 cm x 3.0 cm and 4.0 cm x 4.0 cm at 1.5 and 5.0 cm depths in a solid-waterTM phantom. The measurements have been then compared with GafChromic film, a 2D array ion chamber as well as with MC simulations with DOSXYZnrc and FLUKA.

The use of Volumetric Modulated Arc Therapy (VMAT) is expected to increase, largely due to development of helical tomotherapy. VMAT minimises the occurrence of hotspots and irradiation of critical organs, providing more uniform dose while sparing critical organs. Two important characteristics of VMAT are its dynamic nature and dosimetric variability in radiation delivery. These present considerable challenge for clinical physicists as the implementation of the process contains a number of sources of uncertainty and thus require robust QA. This dissertation describes an evaluation of the currently achievable accuracy in VMAT delivery. Uncertainty in dose determination between primary standards is compared, as well as beam calibration of megavoltage photons at reference field sizes and for small field dosimetry associated with tomotherapy. Additional steps in the radiotherapy process including target volume delineation, evaluation of dose distribution and daily patient treatment (patient setup) have also been considered. The codes of practice currently employed in electron and photon radiotherapy beam dosimetry are well developed, in particular those of the International Atomic Energy Agency (IAEA TRS-398), the American Association of Physicists in Medicine (AAPM TG-51) and the Institute of Physics and Engineering in Medicine (IPEM 2003). For the photon and electron beams studied, the applied protocols show that all measured absorbed doses agree, with differences of less than 2. 0%. For the absorbed dose calibrations using tomotherapy, beam uncertainty in primary standard calibration has been estimated to be 1. 05%. An assessment of uncertainty in target volume delineation has also been considered. The combined uncertainty for the head & neck (H&N) study is 1. 67%, while for the prostate study the combined uncertainty is 5. 57%. Regarding actual beam delivery 15 Delivery QA plans for H&N patients were assessed for a tomotherapy system using Kodak X-Omat V film and an A1SL Ref F92722 ion chamber versus MapCheck2. Gamma matrix distribution was applied to evaluate the difference between measured and computed dose distributions. The combined uncertainty from H&N is 1. 11%, lower than that from the prostate study, which is 1. 16%. Generally, the combined uncertainties for the whole study in head and neck were found to be 2. 35% while for prostate cases, the combined uncertainty is 6.29%.

In recent years, small fields have come to play a key role in advanced radiotherapy, yet protocols to perform dosimetry under small field conditions are still in their infancy. In 2008, the IAEA and AAPM published a formalism [Med. Phys. 35, 5179-5186] recommending the use of point-dose correction factors. This thesis uses Monte Carlo simulations to demonstrate that the values of these correction factors depend strongly on both detector design and field size, as well as other variables such as detector off-axis position and detector azimuthal angle. Mass density is found to be the principal determinant of detector water non-equivalence. Furthermore, it is shown that it is possible to compensate for the mass-density of a detector cavity by incorporating additional components of contrasting mass-density into that detector’s design. For small cavities, such design modifications enable the detector’s small- to large- field response ratio to be matched to that of a “point-like” water-structure: ideal detector performance can be achieved across a variety of irradiation conditions. For existing commercial detectors, a Dose Area Product (DAP) formalism is also developed and shown to be much more robust than the point-dose correction factor approach. In conclusion, correction factor values for existing detector designs depend on a host of variables and their calculation typically relies on the use of time-intensive Monte Carlo methods. This thesis indicates that future moves towards density-compensated detector designs or DAP-based protocols can simplify the methodology of small field dosimetry.

High-intensity focused ultrasound (HIFU) is rapidly emerging as a viable alterna- tive to conventional therapies in the treatment of deep-seated, solid tumours. In contrast to surgical methods, extracorporeal HIFU transducers non-invasively tar- get pathogenic tissue deep beneath the skin, inducing thermal necrosis of a volume of tissue typically coincident with the ultrasound focus. More recently, cavitation activity has been observed to enhance focal heating, whilst providing a unique op- portunity for real-time treatment monitoring. Unfortunately, the stochastic nature of cavitation makes it difficult to initiate and sustain the level of cavitation activity required for enhanced heating, and to confine the spatial extent of cavitation to the focal volume. The overall aim of this thesis is to design and implement a real-time, closed- loop controller for sustaining thermally relevant cavitation within the HIFU focal region. This is intended to improve the speed and reproducibility of tissue ablation, whilst providing clinicians with real-time feedback as to the extent and location of the ablated region. A quantitative relationship between the level of cavitation activity and asso- ciated temperature rise is first sought experimentally, by investigating cavitation- enhanced heating in two different tissue-mimicking materials (TMM) that yield dif- ferent levels of cavitation for the same HIFU exposure conditions. It is found that a minimum level of inertial cavitation activity is required for cavitation-enhanced heating to dominate the heating process, which is achieved in the first material but not the second. However, the introduction of exogenous, artificial nuclei to the second material is seen to augment cavitation levels to the extent that cavitation- enhanced heating becomes dominant. Subsequently, HIFU experimentation is extended to non-perfused, ex vivo bovine liver, into which a variety of cavitation nuclei are introduced to augment cav- itation levels, and hence heating. Commercially available lipid-shelled microbub- bles are contrasted with custom-made sonosensitive nanoparticles for their ability to seed cavitation events, culminating in an empirical relationship between iner- tial cavitation and heating that is common to both types of exogenous nuclei, and which agrees with the in vitro results. Moreover, the abnormally large lesions pro- duced are found to correlate with a broad spatial distribution of inertial cavitation events, as seen on two-dimensional passive acoustic maps. Based on these encouraging results, a novel negative-feedback, real-time con- trol system is implemented to sustain inertial cavitation within the focal region for extended periods of time. The controller is designed to be both asymmetric and adaptive, deploying different feedback gains to adjust the peak rarefactional focal pressure (PRFP), depending on whether cavitation activity is above or below the level required for cavitation-enhanced heating. With active cavitation control in vitro, the associated focal temperature elevation is maintained at a cytotoxic level for 20 seconds using less than half the energy input required in the absence of cavi- tation control. In order to test the applicability of the novel controller to a near-physiological environment, HIFU exposures are eventually performed in a unique normothermic perfused liver model that accounts for both heat advection and nuclei replenish- ment. Following preliminary experimentation, the controller is modified to account for the inherent variability in the cavitation threshold of perfused tissue, whilst the cavitation demand is also increased to account for heat advection. Following these modifications, use of the controller is found to enable greatly improved re- producibility of HIFU-induced lesions compared to those achieved without cavita- tion control, with a lesion size that is directly related to the cavitation demand. A cost-effective method for enabling caviation-enhanced, cavitation-controlled and cavitation-monitored HIFU therapy has thus been developed, which enables suc- cessful tissue ablation at acoustic energies lower than in current clinical use.

The human transferrin receptor (CD71) is a ubiquitously expressed internalising glycoprotein involved in iron homeostasis. Expression of the transferrin receptor is found to be greatly upregulated in tumour cells and, as such, it offers a useful target in the development of immunotherapeutic agents for tumour therapies. This laboratory has developed a Histagged anti-CD71 single-chain variable fragment (scFv) antibody, expressed in Pichia postoris, to be used in the investigation oftargeted radio-immunoconjugates against cancer. The production of an anti-CD71-scFv was confirmed using N-terminal sequencing, and the scFv was purified via a double His-tag using affinity chromatography to produce yields of 13.3mgfl of anti-C071-scFv. Specific binding of the scFv to the human transferrin receptor was evaluated by flow cytometry using C071+ HL-60 leukaemia cells and CHO cells that are CD7r. The anti-CD71-scFv was demonstrated to bind specifically to the CD71 TfR receptor with comparable binding to the monoclonal anti-C071 antibody using flow cytometry. No binding of either antibody to the COJ1- CHO cell line was observed. Saporin, a ribosome inactivating protein, was used to· demonstrate the internalising ability ofthe anti-C071-scFv. Saporin is highly cytotoxic but only if it can reach the cytosol of the target cell. The antiCD71- scFv was able to deliver a non-internalising monoclonal antibody-saporin conjugate intracellularly. This resulted in significant toxicity to CD71+ MCF-7 cells and confirmed that the anti-CD71-scFv could internalise.The anti-CD71-scFv was successfully conjugated to the y and Auger emitting isotope, 1:2.51. 12S1 was selected because the v-rays allow simple monitoring of the binding of the anti-CD71-scFvNal2S1 whilst the Auger electrons provide a potential cytotoxic effect if the radionuclide can get close to the nucleus. The anti-C071- scFv_Nal25 , was shown to retain specific binding ability to its target CD71 receptor, however Clonogenic and Comet assay systems did not show signs of DNA damage and cell cytotoxicity as a result of targeted radio-immunotherapy with the scFv-Naus, conjugate. The anti-CD71-scFv was shown to provide a useful delivery mechanism that is cheap to produce and purify and able to specifically bind and internalise into CD71+ tumour cell s. The isotope 12S1 was unable to demonstrate a cytotoxic effect on targeted cells, most likely due to the formation of monoiodotyrosine residues caused by the degradation of the anti-CD71-scFv intracellularly rapidly diffusing from the lysosome. Further investigation using alternative isotopes and the addition of nuclear localisation and endosomal escape sequences is warranted.

In this thesis, novel Case-Based Reasoning (CBR) methods were developed to be included in CBRDP (Case-Based Reasoning Dose Planner) -an adaptive decision support system for radiotherapy dose planning. CBR is an artificial intelligence methodology which solves new problems by retrieving solutions to previously solved similar problems stored in a case base. The focus of this research is on dose planning for prostate cancer patients. The records of patients successfully treated in the Nottingham University Hospitals NHS Trust, City Hospital Campus, UK, were stored in a case base and were exploited using case-based reasoning for future decision making. After each successful run of the system, a group based Simulated Annealing (SA) algorithm automatically searches for an optimal/near optimal combination of feature weights to be used in the future retrieval process of CBR. A number of research issues associated with the prostate cancer dose planning problem and the use of CBR are addressed including: (a) trade-off between the benefit of delivering a higher dose of radiation to cancer cells and the risk to damage surrounding organs, (b) deciding when and how much to violate the limitations of dose limits imposed to surrounding organs, (c) fusion of knowledge and experience gained over time in treating patients similar to the new one, (d) incorporation of the 5 years Progression Free Probability and success rate in the decision making process and (e) hybridisation of CBR with a novel group based simulated annealing algorithm to update knowledge/experience gained in treating patients over time. The efficiency of the proposed system was validated using real data sets collected from the Nottingham University Hospitals. Experiments based on a leave-one-out strategy demonstrated that for most of the patients, the dose plans generated by our approach are coherent with the dose plans prescribed by an experienced oncologist or even better. This system may play a vital role to assist the oncologist in making a better decision in less time; it incorporates the success rate of previously treated similar patients in the dose planning for a new patient and it can also be used in teaching and training processes. In addition, the developed method is generic in nature and can be used to solve similar non-linear real world complex problems.

Antiprotons have been proposed for use in radiotherapy due to their similar energy deposition in water to protons except for an increased dose near the Bragg peak due to antiproton annihilation at rest. There has been skepticism about the use of antiprotons for therapy therefore radiobiological investigations are required to gain a better understanding of the biological effectiveness of antiprotons along the beam path and in the out-of-field regions. Antiproton induced DNA damage in AG01522 fibroblast cells has been investigated using the yH2AX assay. DNA damage and repair have been correlated with cell killing and sub lethal damage. Analogous experiments were conducted with proton and carbon-ion beams that are already used for radiotherapy. DNA damage in cells in the middle of the spread-out Bragg peak persisted longer than that caused by X-rays, plateau anti protons or protons but were repaired quicker than those caused by carbon-ions. Antiproton induced foci appear also larger than those induced by the other radiation modalities investigated. The persistence of foci has been related to LET and is correlated with increased biological effectiveness for cell killing and micronucleus/chromosome aberration formation. The effects outside radiation fields have also been investigated. This study suggests that radiation induced bystander effects in the AG01522 cell line may be LET dependent and appear at late time points after radiation. Investigation into the impact of antiproton annihilation secondary particles outside the primary beam revealed a dose dependent increase in DNA damage at 26 h after exposure in cells that also shared media with cells in the beam at the time of irradiation. This was only significant however for a single dose point. Cells that did not share media with the cells in the beam during the irradiation had low levels of DNA damage that was only significant for 5.56 and 6 Gy doses.

Low linear energy transfer (LET) ionizing radiation as gamma and X-rays is widely used in the modem medicine for diagnostic and treatment purposes. Despite all the advantages that it gives for the early diagnosis and in the radiotherapy treatment of cancer, there are still unclear aspects about the mechanisms of the radiation effects in human tissue. Of particular interest is the detailed pathway which the directly irradiated cells use to communicate to their neighbours and its possible implications for radiotherapy applications. The aim of this project is to study the spatio-temporal signalling from irradiated to non- irradiated cells using in vitro 3D tissue models. For evaluation of radiation induced effects we used conventional 225 kVp X-ray and lead shielding to observe the effects in the non-targeted cells. Additionally we applied the novel 30 kVp micro collimator that could irradiate samples in wide 1-10 urn lines. The application of this targeted radiation source together with the shielding irradiation set up will cast light on the effects induced by localized radiation exposures and the signalling from the irradiated to non-irradiated cells using 3D organotypic skin as a model. Due to its fast cell turnover, the human epidermis is extremely sensitive to IR. This has a limiting effect on the radiotherapy as severe normal skin responses can delay treatment and even decline patients from radiotherapy. The current work is aiming to reveal the mechanisms of DNA damage, repair and their later consequences for the differentiation and development of inflammatory-like response in the irradiated and surrounding areas within the 3D organotypic skin model. We investigated use of inhibitors of pro-inflammatory pathways such as the transcription factor NF-KB and its downstream target COX-2, in order to reduce the signal transduction from the irradiated to non irradiared cells and to reduce the inflammatory responses in the surrounding normal tissue. Similar methods of control of the signal diffusion could be applied in the radiotherapy to reduce the inflammatory skin responses and decrease the range of the late side effects developing from the chronic inflammation that could further lead to ulceration and skin necrosis.

This thesis describes a new design method for a radio frequency quadrupole (RFQ), and its application to the first stage of acceleration for carbon ions in the PAMELA injector. Radiotherapy is a valuable form of cancer treatment, but current methods using photons or electrons make it difficult to deliver an adequate dose to the tumour without damaging healthy surrounding tissue and organs. Charged hadron beams, such as protons and carbon, deposit most of the dose at the Bragg peak, which can be aligned with the tumour. This allows higher doses to treat the cancer while minimising damage to healthy surrounding tissue and organs. The PAMELA project (part of the BASROC consortium) aims to design new charged particle therapy (CPT) facilities using non-scaling fixed-field alternating-gradient accelerators (ns-FFAGs). This new technology offers significant advantages over both cyclotrons and synchrotrons for CPT. The injector for the PAMELA FFAG accelerator includes separate pre-acceleration chains for protons and carbon ions, culminating in a shared injection system into the first FFAG ring. Carbon ions are pre-accelerated by an RFQ and a short linear accelerator (linac). This thesis details the creation of an integrated system of software packages and custom code, which facilitates the design of RFQ vane tips, utilising computer-aided design (CAD) models for both simulation and manufacture, accurate multi-physics modelling of the electric field and particle tracking simulations. This design process is described, along with benchmark results for the Front- End Test Stand (FETS ) RFQ and application of the code in optimising a new RFQ design for PAMELA.

The fluence correction factor, which accounts for the loss of primary protons and the production of secondary particles due to different non-elastic nuclear interactions at water equivalent depths in different phantom materials compared to water is an important parameter for the dose conversion in clinical proton dosimetry between any phantom material and water. Non-elastic nuclear interactions introduce uncertainties in the standard absorbed dose-to-water in radiotherapy. This thesis is part of an ongoing project at the UK National Physical Laboratory (NPL) focussed on the development of graphite calorimeters for proton dosimetry. The fluence correction factor was investigated to give accurate dose conversions from dose-to-graphite in a graphite phantom to dose-to-water in a water phantom. The fluence correction factors at water equivalent depths have been studied for various dosimetric materials including A-150 tissue equivalent, polymethyl methacrylate (PMMA), aluminium and copper with respect to water and with respect to graphite. The water equivalence of materials such as Plastic Water (PW), Plastic Water Diagnostic Therapy (PWDT) and solid water (WT1) phantoms was evaluated using a 60 MeV proton beam at the Clatterbridge Centre for Oncology. Plastic-water phantoms are widely used in radiotherapy as a substitute for water, in particular for non-reference dosimetry. However, while they are usually made ‘water equivalent’ for a particular beam type, they are not universally water equivalent due to their different elemental composition and associated different proton interaction cross sections (compared to water). Numerous studies of the water equivalence of plastic-water phantoms have been reported for photon and electron beams, but none with clinical proton beams. In the latter, non-elastic nuclear interactions take place which could potentially influence the water equivalence. This thesis evaluates the fluence correction factor at equivalent depths for proton energies of 60 MeV and 200 MeV, with respect to both water and graphite. This work was performed using analytical model calculations (which incorporate the ICRU-49 (1993) stopping power data tables and ICRU-63 (2000) for the total nuclear interaction cross sections); Monte Carlo simulations using the FLUKA 2008. 3 code; and also experimental work at the Clatterbridge Centre for Oncology (CCO) 60 MeV with both modulated and unmodulated proton beams. The analytical calculations for primary protons indicate an increase in the fluence correction at both low and high energies compared to the Monte Carlo simulations. When the secondary charged particle were considered in the calculation, the fluence correction factor with respect to water was in general close to the unity for graphite, A-150, PMMA, aluminium and plastic-water materials in 60 MeV mono-energetic beam. For proton energies of 200 MeV, the fluence correction was found to increase to a the order of a few percent. The experimental finding for modulated and un-modulated 60 MeV protons showed that the fluence correction factor with respect to water is close to unity for graphite and PWDT with an uncertainty of 0. 2% at 1o. The derived fluence correction with respect to graphite was also close to the unity for A-150 and plastic-water materials, however, it was found to increase with depth to approximately 4% and 6% for aluminium and copper respectively (in modulated beam). In general, the experimental results for modulated and unmodulated 60 MeV proton beams show good agreement with the Monte Carlo simulations for modulated and un-modulated beams, yielding small fluence corrections, within the statistical uncertainty. For 200 MeV protons, the Monte Carlo simulations showed that the correction with respect to water increased with penetration depth giving values of up to 4% for graphite and 1. 5% for A-150, PMMA, aluminium, copper and plastic-water materials. The fluence correction with respect to graphite was found to vary with penetration depth and hence it can be concluded that fluence correction factors need to be applied to ensure accurate dosimetry for all of the materials used in the current work with a 200 MeV proton beam.

A 3D non-contact real-time multi sensor fringe measurement system is proposed in this research. The system is designed to help radiotherapists detect human body measurements and motions during the cancer radiotherapy treatment process in real-time. The ability to detect body movements will help radiotherapists to accurately estimate the actual radiation dose that was delivered to the tumour volume. The researchers at JMU built a three-sensor system that covers 3600 around the object so that the system can have full visibility around the human body under treatment. Each sensor consists of one camera and one projector and each sensor works on its own exclusive light bandwidth to enable all sensors to work concurrently without affecting each other's operation. Each sensor is connected to its own data processing unit that controls its operation and carries out data processing tasks and all three data processing units are connected to a main central computer that controls and coordinates the operation of the three sensors. The author developed a novel empirical calibration approach to calibrate the three sensors concurrently; the proposed calibration approach solves the depth calibration problem and the perspective problem to provide the system with the ability to measure 3D shapes in an absolute physical coordinate system that is consistent with the coordinate system of the radiotherapy treatment machine. The author also implemented two algorithms for absolute 3D body shape measurements. The first is a multi-frame algorithm using the phase-stepping technique while the second is a single-frame algorithm that is based on the Fourier Fringe Analysis technique. A performance comparison between these two methods is given in the literature. Finally, the author describes measurement validation and error reporting methods to provide the system with the ability to estimate the quality of its own measurements, to detect errors and report failures in the measurement process. This feature is very crucial to system operation especially in sensitive applications like cancer treatment as it provides qualitative and quantitative measures of validity to the measurements. This research has resulted in a practical real-time system that is implemented at both, the LAB and Christie Hospital Manchester. The system has been thoroughly tested and it has shown very good performance in terms of reliability, accuracy, usability and speed.

In the various brachytherapy techniques the intent is to deliver as high a tumour dose as possible, limited only by surrounding normal tissue tolerance. The main feature of the techniques is very steep dose gradients, representing a potential limiting factor in accurate dose distribution measurements around sources. Dose distributions at distances less than 1 cm are therefore normally generated using either validated Monte Carlo (MC) simulations or standard dose calculation formalisms, for example that of AAPM TG 43, while dose measurements can only be performed at larger distances, normally greater than 1cm from the outer dimensions of the source encapsulation Ge-doped silica fibres are a viable thermoluminescent dosimetry (TLD) system, providing good spatial resolution of approximately 120 μm, sensitive response to ionizing radiations, large dynamic dose range, good reproducibility and reusability, dose rate independence, minimal fading, resistance to water and low cost. Dosimetric characterisation of commercial Ge-doped silica fibres have been obtained by subjecting them to kilovoltage therapeutic x-ray radiation beams, verifying their use for brachytherapy sources; dose response, reproducibility and fading at 90 kVp and 300 kVp have been investigated. Central-axis depth doses have been obtained at the two accelerating potentials using different field size applicators, measurements being made using the fibres in both water and a GAMMEX RMI 4571 solid water phantom. Comparison has been made with central-axis depth doses, measured using a 0.6 cm3 graphite-walled ionisation chamber data and British Journal of Radiology Supplement 25 tabulated values (both in water). Ge-doped optical fibre dosimeters show good dosimetric response for low photon energies. These desirable characteristics support the use of these TL fibres as dosimeters for brachytherapy applications. Ge-doped optical fibre TL dosimeters have been used to measure the dose distribution around two Low Dose Rate (LDR) 125I seeds; model 6711, the new thinner model 9011 and a High Dose Rate (HDR) 192Ir (MicroSelectron V2) source at proximal distances down to 1 mm, measured in a Perspex medium. The anisotropy has also been measured in Perspex, for distances from 10 to 100 mm from a LDR 125I seed model 6711 centre, in 10 mm increments and at angles 10 to 90 in 10 increments from the seed central axis. Measured doses have been compared with calculations and treatment planning system (TPS) predicted doses for the same locations. Monte Carlo simulations were obtained using the EGSnrc \\ DOSRZnrc codes and TPS predicted doses were obtained using the system VariSeed V8.0.2. For 125I seed model 6711, the measurements agree with simulations to within 2.3 % +- 0.3 % along the transverse and perpendicular axes and within 3.0 % +- 0.5 % for measurements investigating anisotropy in angular dose distribution. Measured and Veriseed TM brachytherapy treatment planning system (TPS) values agreed to within 2.7 % +- 0.5 %. For the new thinner 125I model 9011, dose measurements were in good agreement with simulations to within 2.1 +- 0.2 %, while dose measurements and doses obtained through use of the Variseed TPS agreed well, to within 2.2 +- 0.5%. The above work has therefore demonstrated the applicability of Ge-doped optical fibres for use in brachytherapy.

The latter two decades of the last century saw significant improvements in External Beam Radiotherapy (EBRT), moved primarily by the advances in imaging modalities and computer-based treatment planning. These advances led to introducing the addition of a fourth dimension, time, to the three-dimensional EBRT arena. This new era in EBRT brings with it challenges and opportunities, in particular to compensate for the effect of respiratory-induced target motion and enhancing treatment delivery. Thus, characterising and modelling respiratory motion is of major importance in this research area. This thesis aims to enhance the understanding and control the effect of respiratory motion. As part of this work, the first principal component analysis (PCA) of respiratory motion is presented, as a basis for compactly and visually representing respiratory style and variation. These studies can be divided into two main aspects: firstly, understanding and characterising respiratory motion as the basis of any further steps towards compensating respiratory motion and secondly, utilising this knowledge in predicting and correlating internal and external respiratory motion in the abdominal thoracic region. This work has been developed starting with a piecewise sinusoidal model in an Eigenspace for modelling. Adaptive kernel density estimation (AKDE) for prediction and finally Canonical Correlation Analysis (CCA) for external-internal target correlation. A comparative study between these proposed approaches and state-of-the-art prior works showed promising results in terms of accuracy and computational efficiency: 20% error reduction compared to support vector regression (SVR) and kernel density estimation (KDE) and a significant reduction in computation speed during training stage. This journey into modelling and predicting respiratory behaviour has naturally raised questions of how best to track external motion. The need to track the surface with more than one marker, established within the aforementioned PCA analysis, motivates the desire for markerless tracking. Therefore, two different markerless systems have been studied, as potential solutions for this area, combined with a mesh model of the anterior surface. This suggests that the Microsoft Kinect camera is a promising low-cost technology for makerless respiratory tracking with less than 3. 1 +- 0. 6 mm accuracy.

The introduction in Radiation Oncology of x-ray beams fluence modulation, the treatment technique known as Intensity Modulated Radiation Therapy (IMRT), is leading to the flourishing of new and increasingly sophisticated treatments. It is within this context that delivery systems have been evolving from static to rotational IMRT techniques through which significant advantages have occurred in terms of treatment plan quality, delivery efficiency and accuracy, although paying the price of longer calculation times for the plan optimization. The point has been reached where the perceived advantages of rotational IMRT techniques, for which some companies have marketed therapy systems with different architecture from that of conventional linear accelerators, have led users to question whether the established and more conventional systems are becoming obsolete. However, the newly available methods of delivering Intensity Modulated Arc Therapies (IMAT) using conventional accelerators, an advanced form of rotational IMRT that combines multiple arcs with variable fluence and gantry speed, seem to have provided a preliminary answer to this concern. Although it is difficult to know which of these treatment modalities will be discontinued in the near future, it is clear that the rotational IMR T is expected to become increasingly important. Therefore, the problem of understanding which are the strengths of these techniques, or the most effective methods (forward or inverse-planning based) of their treatment planning procedures, as well as the most robust and effective systems for verifying dosimetrically such rotational deliveries can be considered current research topics. As a results, different aspects of rotational IMRT techniques have been investigated in this work, starting with the pre-clinical dosimetry of IMAT therapies, passing through the planning procedures also in comparison with static IMR T, and advancing to a special application of 'rotational IMRT': the simulation of radiobiologically optimised, voxel-based dose-painting, guided by the metabolic tumour imaging. In particular we have worked on: two methods for the pre-clinical dosimetry of IMA T treatments using a matrix detector of ionization-chambers and an electronic portal imaging device, a forward and an inverse-planning approach for simulating IMAT treatments, a ranking of plans simulated with static and rotational IMRT modalities on prostate tumour. The high conformality achievable by rotational IMRT, as well as its potential to deliver selectively different doses inside a heterogeneous target volume, together with the image guidance capabilities of the newest therapy units, makes arc modulation the most appropriate and suitable instrument for assessing future "dose painting" treatments. In this regard, two radiobiological objective functions for guiding the dose redistribution inside a group of prostate tumours according to their estimated clonogenic density distribution (based on Position Emission Tomography imaging) were developed, compared and analysed.

The state-of-the-art radiotherapy delivery treatments available today require that the intended dose distributions delivered are verified by volumetric gel dosimetry. The development of tissue equivalent gel dosimeters that provide an integrated assessment of the dynamic treatments, are primarily imaged with Magnetic Resonance Imaging (MRI). This thesis describes the dual development and assessment of an optical tomographic scanner and normoxic gel dosimeter. MRI centers are currently limited in both time and resources in providing the routine imaging necessary for treatment verification. An alternative bench top imaging modality has been designed, built and developed to provide both complementary and comparable observations to MRI. It is hoped that this cost effective optical imaging system could alleviate this technological reliance. The optical tomography scanner is evaluated from a series of investigations into the capabilities and limitations of optical tomographic imaging used in conjunction with gel dosimetry. Previously, the manufacture of gel dosimeters required anoxic environments in which the presence of oxygen in the dosimeter is limited. This requirement limited the production of gel dosimeters to chemistry laboratories that possessed the required technical expertise. MRI and optical imaging have been used to investigate the properties, dose response and the batch-to-batch reproducibility of a normoxic MAGIC gel dosimeter. The results obtained are encouraging having shown successfully reconstructed optical images obtained from various dose distributions delivered to the MAGIC gel dosimeter.

Several aspects of the IMRT treatment chain are evaluated with a view to improving the accuracy with which the treatment can be delivered and also the radiobiological outcome for the patient. A safe, non-invasive way of evaluating patient repositioning for multi-fraction treatments is developed and presented, with results highlighting the head-and-neck immobilisation system that provides the best results at Addenbrooke's radiotherapy centre. Previously published dose evaluation metrics are studied in depth, identifying ways in which they differ. A new method of calculating the popular Gamma index is proposed, along with a new Kappa index which can highlight areas of dose mismatch more readily than the Gamma index. Using a specially developed dose calculation system, systematic errors found with the IMRT treatment machines at Addenbrooke's are simulated to determine the dose differences created by these errors, which are then evaluated using the Kappa index with typical tolerances used by previous authors. The concept of equivalent uniform dose (EUD) is then used to assess whether the tolerances for distance and dose are equivalent to each other. They are found not to be equivalent, and better relative values of the two quantities are suggested for use in composite indices. The use of the EUD is extended further into analysing the equivalent dose differences of the treatment delivery errors previously calculated. It is found that the equivalent dose to the target volume is changed by more than the composite indices indicate. The EUD is then used to calculate normal tissue complication probabilities, the probability of uncomplicated control and therapeutic gain. It is found that the dose errors predicted can actually be beneficial to the patient outcome, although not always. It is concluded that dose evaluation for complex treatments such as IMRT should be more radiobiologically-based in order to assess patient outcomes properly.

High resolution voxel-based phantoms were used to assess organ doses from neutron external exposure. The segmented images of the Zubal voxel-based phantoms were obtained from the Imaging Science Research Laboratories at Yale University School of Medicine. The phantoms data were incorporated into MCNP4C2 and MCNPX Monte Carlo codes. There are twofold dose calculations in this study using monodirectional monoenergetic neutron beams in the energy range of 10 -9 (thermal) to 20 MeV, plus an extra calculation using a Maxwell fission spectrum source, under three different source irradiation configurations: anterior-posterior, posterior-anterior, and left lateral. Comparisons between the fractional dose contributions (in percent) from photon and neutron are taken into account in the determination of the total effective dose. The comparison with mathematical the MIRD phantom and the VIPMAN voxel phantom show partial agreement for neutron effective dose calculations and huge differences for organs absorbed doses. The differences between the three phantoms neutron exposure simulations are discussed and further limitations of voxel-based tomographic phantom are investigated. The future work at the end of this thesis presents a voxel-based eye phantom for high energy proton therapy with initial simulation of a proton beam.

The research presented in this thesis investigates a method of objectively quantifying tissue stiffness post radiotheiapy. The project has involved the design, development and modification of an indentation system that was compared with the currently used subjective clinical assessment. The breast has been chosen as the prime site for investigation in the light of the high value placed on cosmesis by patients, the ease of access to these tissues, and the availability of the untreated breast to serve as a control.

The work presented in this thesis developed from the quality assurance for the START trial. This provided a unique opportunity to perform measurements in a breast shaped, soft tissue equivalent phantom in over 40 hospitals, representing 75% of the radiotherapy centres in the UK. A wide range of planning systems using beam library, beam model and convolution based algorithms have been compared. The limitations of current algorithms as applied to breast radiotherapy have been investigated by analysing the results of the START quality assurance programme, performing further measurements of surface dose and setting up of a Monte Carlo system to calculate dose distributions and superficial doses. Measurements in both 2D and 3D breast phantoms indicated that the average measured dose at the centre of the breast was lower than that calculated on the planning system by approximately 2%. Surface dose measurements showed good agreement between measurements and Monte Carlo calculations with values ranging from 6% of the maximum dose for a small field (5cmx5cm) at normal incidence to 37% for a large field (9cmx20cm) at an angle of 75°. Calculation on CT plans with pixel by pixel correction for the breast density indicated that monitor units are lower by an average 3% compared to a bulk density corrected plan assuming a density of 1g.cm-3. The average dose estimated from TLD in build-up caps placed on the patient surface was 0.99 of the prescribed dose. This shows that the underestimation of dose due to the assumption of unit density tissue is partially cancelled by the overestimation of dose by the algorithms. The work showed that simple calculation algorithms can be used for calculation of dose to the breast, however they are less accurate for patients who have undergone a mastectomy and in regions close to inhomogeneities where more complex algorithms are needed.