Magnetic resonance imaging is utilized as an important tool in radiation oncology for delineation of healthy and cancerous tissues, and evaluating the functionality of those tissues, structures, and organs. Currently, the clinical imaging protocol at Virginia Commonwealth University includes anatomical imaging for tissue and structure delineation, and to observe treatment induced changes. Diffusion weighted imaging (DWI) is also acquired for calculation of apparent diffusion coefficient (ADC) values to provide quantitative information on tissue diffusivity and microstructure. However, anatomical images and ADC values may not display the true extent of changes in tissue. This work seeks to further utilize the capabilities of MRI and expand its role in treatment response monitoring for liver cancer patients treated with stereotactic body radiotherapy (SBRT). To do so, an imaging protocol and image analysis methodology to evaluate treatment changes on pre- and post-treatment image sets was developed. An extension of DWI, termed intravoxel incoherent motion (IVIM) imaging, was utilized to quantitatively assess levels of perfusion and diffusion within the liver and tumor. Acquisition of high-quality diffusion weighted images of the liver necessitated the development of an MR safe respiratory motion management device, which was designed, constructed and evaluated in this work. An imaging protocol was developed providing anatomical and functional images of the liver, acquired under breath hold, utilizing the respiratory motion management device. An IVIM parameter calculation and texture analysis workflow was developed using MATLAB, and applied to acquired data sets from multiple studies, including past clinical cases, investigator, healthy volunteer, and liver cancer patient . Differences in IVIM and texture analysis parameters were investigated for healthy and diseased tissue, and for select dose regions from pre- and post-treatment imaging sessions. Significant differences, at a voxel level, were found between healthy and diseased tissue, and pre- and post-treatment volumes, for multiple parameters, including apparent diffusion coefficient, pure diffusion, and perfusion, as well as for various texture features. Overall, this study showed the potential of IVIM and texture analysis to be used for discriminating between healthy and diseased tissues in the liver, and for indication of treatment response.

AB S TRACT purpose : To further investigate the effects of respiratory motions on CBCT imaging, as well as 4D-CT examinations, with a future goal of using obtained results to implement new methods for individual margins and daily matching procedures into routine clinical practice. background : Since the implementation of CBCT combined with modern accelerators, a higher degree of accuracy has been made possible in RT. However, due to the slow gantry speed of linear accelerators, the imaging procedure of CBCT is a slow process which is thereby degraded by internal motion such as respiration. material and methods : Attain patient specific respiratory motion patterns from CBCT projection data of previous examinations. Utilize this data to perform simulations for both CBCT and 4D-CT using a steering system which allows for arbitrary motion patterns in the longitudinal direction. results : Various imaging with CBCT showed that the resulting images during respiratory motion, can be described by the Probability Density Function of the motion for as long as it does not cause related distortions. This also meant that convolution could be implemented as a model to estimate the CBCT images during oscillation, knowing the object and motion pattern. The 4D-CT examinations using the steering system showed that irregular motion patterns were less accurately described than regular patterns, making the actual motion an important feature to combine together with the measured amplitude. conclusions : It was made clear that CBCT images can be described by the PDF, and thus can be seen as a Color Intensity Projection of the object position. Also it has been shown that the projection data of CBCT images contains valuable information about the respiratory motion of the patient. Another conclusion is that with the help of fiducials, the position of the target within the respiratory cycle can be determined relative to the 4D-CT examination, enabling further input data as to the daily matching procedure, proper applied margins as well as dose to the OAR.

The search for the optimal choice of treatment time, dose and fractionation regimen is one of the major challenges in radiation therapy. Several aspects of the radiation response of tumours and normal tissues give different indications of how the parameters defining a fractionation schedule should be altered relative to each other which often results in contradictory conclusions. For example, the increased sensitivity to fractionation in late-reacting as opposed to early-reacting tissues indicates that a large number of fractions is beneficial, while the issue of accelerated repopulation of tumour cells starting at about three weeks into a radiotherapy treatment would suggest as short overall treatment time as possible. Another tumour-to-normal tissue differential relevant to the sensitivity as well as the fractionation and overall treatment time is the issue of tumour hypoxia and reoxygenation. The tumour oxygenation is one of the most influential factors impacting on the outcome of many types of treatment modalities. Hypoxic cells are up to three times as resistant to radiation as well oxygenated cells, presenting a significant obstacle to overcome in radiotherapy as solid tumours often contain hypoxic areas as a result of their poorly functioning vasculature. Furthermore, the oxygenation is highly dynamic, with changes being observed both from fraction to fraction and over a time period of weeks as a result of fast and slow reoxygenation of acute and chronic hypoxia. With an increasing number of patients treated with hypofractionated stereotactic body radiotherapy (SBRT), the clinical implications of a substantially reduced number of fractions and hence also treatment time thus have to be evaluated with respect to the oxygenation status of the tumour. The perhaps most promising tool available for the type of study aiming at determining the optimal SBRT approach with respect to fractionation is radiobiological modelling. With clinically-derived tissue-specific radiobiological parameters and well-established survival models, in silico modelling offers a wide range of opportunities to test various hypotheses with respect to time, dose, fractionation and details of the tumour microenvironment. Any type of radiobiological modelling study intended to provide a realistic representation of a clinical tumour should therefore take into account details of both the spatial and temporal tumour oxygenation. This thesis, consisting of papers I-III and a summary, presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various radiation qualities, fractionation schemes, oxygenation levels and dynamics using different survival models. The results of this work indicate that hypoxia and its dynamics play a major role in the outcome of both photon and carbon ion radiotherapy, and that neglecting the oxygenation status of tumours treated with SBRT may compromise the treatment outcome substantially. Continued to include clinical studies on the impact of hypoxia on the treatment outcome in lung cancer patients treated with SBRT, this project will hopefully advance the evolution towards routinely incorporating functional imaging of hypoxia into treatment planning. This is ultimately expected to result in increased levels of local control with more patients being cured from their cancer.

Tumours are characterised by unorganised vasculature, which often results in hypoxic regions. Hypoxia is a common cause for photon radiotherapy (RT) treatment failure, as hypoxic cells require up to 2-3 times higher doses compared to well-oxygenated cells for the same effect in terms of cell kill. The increase in dose that would be required to treat the tumours of cancer patients is limited by the radiation sensitivity of surrounding normal tissues. Using carbon ions instead of photons, the radiation dose can be conformed to the tumour to a much higher degree, resulting in an improved sparing of normal tissues. In addition, carbon ions have a much higher radiobiological effectiveness near the end of their range, which is positioned in the tumour. Also, the radiation modes of action leading to cell death when carbon ions interact with living tissues, are less sensitive to the oxygen status compared with the action modes of photons. The focus of this thesis lies in the development of models for the computation of the cell surviving fraction and tumour control probability (TCP) in hypoxic tumours after photon and carbon ion RT. The impact of fractionation was evaluated with regard to possible spatial changes in oxygenation, both for stereotactic body RT and for carbon ion RT. The feasibility of a method to determine and deliver the optimal photon dose for achieving a high TCP according to spatial variations in radiation sensitivity was evaluated in a treatment planning study. The radiobiological models were finally used for the theoretical quantification of the gain in using carbon ions instead of photons. The results show that there are great possibilities to increase the number of positive outcomes of radiation treatment of tumours if the key influential factors are taken into account, such as level and distribution of hypoxia, radiation quality and choice of fractionation schedule. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows; Paper 3: Manuscript; Paper 4: Epubl ahead of print; Paper 5: Manuscript</p>

The use of stereotactic body radiation therapy employing few large fractions of radiation dose for the treatment of non-small cell lung cancer has been proven very successful, high values of tumour control probability (TCP) being clinically achieved. In spite of the success of the fractionation schedules currently used, there is a tendency towards reducing the number of fractions for economical and practical reasons, and also for maximizing the comfort of the patients. It is therefore the main aim of this thesis to investigate the impact of a severely reduced number of fractions on the tumour control probability for tumours that contain hypoxic areas. The impact on TCP of other factors such as hypoxic fraction, distribution of the oxygen partial pressure and location of the hypoxic volume within the tumour were also investigated. The effect of tumour motion due to breathing was included and evaluated using Cone Beam Computed Tomography (CBCT) data from patients imaged with internal markers in the liver and pancreas. The results clearly showed that in the presence of hypoxia, TCP is seriously compromised if there is not enough time for reoxygenation between fractions. A reduction in the number of fractions of just one fraction may require an increase of several Gy per fraction to obtain a similar TCP. The diaphragmatic tumour motion range showed little influence on TCP provided that the PTV encompassed all tumour positions. The dose delivered to the PTV margin was found not to be the only factor that is significant for local control, the average dose correlated better with TCP. The agreement of the results of this work with clinical results also serve as a strong indicator that inter-fraction reoxygenation is an important process in real-life patients treated with stereotactic body radiotherapy.

Umeå University Hospital has acquired a new treatment planning system, RayStation, for radiotherapy. It has a different set of dose calculation algorithms that require new planning strategies for stereotactic lung cancer treatments. This \paper{} has two parts and the first investigates the Monte Carlo algorithm, recalculating doses for 21 historical treatments, and finds that it is slow but fast enough to be used and that it reports dose coverage that is usually lower than that of simpler algorithms, particularly for small tumours in low density lungs. The second part investigates the performance of four alternative planning methods: a straight forward PTV/ITV based method, a method using density override of the PTV, an ITV based semi-robust method and a fully robust method treating both setup margins and breathing motion robustly. The new methods are tested on 12 historical cases and are compared, using robust evaluation, to each other and the original plans. The first three are found to all be viable alternatives, while the fully robust method, while impressive, is found not to be a practical alternative at this time. / Norrlands Universitetssjukhus har skaffat ett nytt dosplaneringssystem, RayStation, till radioterapin. Det har en annan uppsättning dosberäkningsalgoritmer som kräver en ny planeringsstrategi för stereotaktisk lungcancerbehandling. Den här rapporten innehåller två delar och den första undersöker Monte Carlo-algoritmen genom att räkna om doserna för 21 tidigare behandlingar. Den visar sig vara långsam men snabb nog för att vara användbar och den rapporterar lägre dostäckning än enklare algoritmer, särskilt för små tumörer i lungor med låg densitet. Den andra delen undersöker fyra alternativa planeringsmetoder: en baserad på PTV och ITV utan krusiduller, en dito med s.k. override av PTVs densitet, en ITV-baserad med robust hantering av setup-marginaler och en helt robust metod med robust hantering av både marginaler och andningsrörelser. De nya metoderna testas på 12 tidigare behandlingar och jämförs, medelst robust utvärdering, med varandra och originalplanerna. De tre första visar sig alla vara goda alternativ medan den helt robusta, som visserligen är imponerande, inte är praktiskt användbar än.

No description available.