In modern, advanced radiotherapy (e.g. intensity modulated photon radiotherapy, IMXT) the delivery time for each fraction becomes prolonged to 10-20 minutes compared with the conventional, commonly 2-5 minutes. The biological effect of this prolongation is not fully known. The large number of beam directions in IMXT commonly leads to a large integral dose in the patient. Electrons would reduce the integral dose but are not suitable for treating deep-seated tumour, due to their limited penetration in tissues. By combining electron and photon beams, the dose distributions may be improved compared with either used alone. One obstacle for using electron beams in clinical routine is that there is no available treatment planning systems that optimise electron beam treatments in a similar way as for IMXT. Protons have an even more pronounced dose fall-off, larger penetration depth and less penumbra widening than electrons and are therefore more suitable for advanced radiotherapy. However, proton facilities optimised for advanced radiotherapy are not commonly available. In some instances electron beams may be an acceptable surrogate. The first part of this study is an experimental in vitro study where the situation in a tumour during fractionated radiotherapy is simulated. The effect of the prolonged fraction time is compared with the predictions by radiobiological models. The second part is a treatment planning study to analyse the mixing of electron and photon beams for at complex target volume in comparison with IMXT. In the next step a research version of an electron beam optimiser was used for the improvement of treatment plans. The aim was to develop a method for translating crude energy and intensity matrices for optimised electrons into a deliverable treatment plan without destroying the dose distribution. In the final part, different methods of treating the spinal canal in medulloblastoma were explored in a treatment planning study that was evaluated with biological models for estimating risks for late radiation effects. The effect on cell survival of prolonging fraction time at conventional doses/fraction is significant in an in vitro system. This effect is underestimated by biological models. Prolonging the fraction time will spare tissues with a fast DNA repair. Thus, there is a risk for sparing tumours. The mixed electron and photon beam technique has the potential to treat deep-seated tumours. Compared with IMXT the number of beams can be reduced and as a consequence, the time for each fraction could be kept shorter. The integral dose in the patient will also be lower. The mixed beam technique could potentially be further improved if automatic optimisation for electrons was available. The results suggest that optimisation and segmentation can be automated, and a deliverable treatment plan can be obtained with simple procedures without destroying the quality of the dose distribution. The integral dose in patients may lead to late radiation side effects. In childhood cancers the risk for development of radiation induced cancers is a reality and the integral dose outside the target volume should be minimised. Based on models for cancer induction, protons show the lowest risk while electrons have some benefit compared with different photon techniques. All methods are able to similarly well treat the target volume.

Thesis (MScEng (Applied Mathematics))--University of Stellenbosch, 2006. / This thesis investigates the various components required for the development of a patient position verification system to replace the existing system used by the proton facilities of iThemba LABS1. The existing system is based on the visual comparison of a portal radiograph (PR) of the patient in the current treatment position and a digitally reconstructed radiograph (DRR) of the patient in the correct treatment position. This system is not only of limited accuracy, but labour intensive and time-consuming. Inaccuracies in patient position are detrimental to the effectiveness of proton therapy, and elongated treatment times add to patient trauma. A new system is needed that is accurate, fast, robust and automatic. Automatic verification is achieved by using image registration techniques to compare the PR and DRRs. The registration process finds a rigid body transformation which estimates the difference between the current position and the correct position by minimizing the measure which compares the two images. The image registration process therefore consists of four main components: the DRR, the PR, the measure for comparing the two images and the minimization method. The ray-tracing algorithm by Jacobs was implemented to generate the DRRs, with the option to use X-ray attenuation calibration curves and beam hardening correction curves to generate DRRs that approximate the PRs acquired with iThemba LABS’s digital portal radiographic system (DPRS) better. Investigations were performed mostly on simulated PRs generated from DRRs, but also on real PRs acquired with iThemba LABS’s DPRS. The use of the Correlation Coefficient (CC) and Mutual Information (MI) similarity measures to compare the two images was investigated. Similarity curves were constructed using simulated PRs to investigate how the various components of the registration process influence the performance. These included the use of the appropriate XACC and BHCC, the sizes of the DRRs and the PRs, the slice thickness of the CT data, the amount of noise contained by the PR and the focal spot size of the DPRS’s X-ray tube. It was found that the Mutual Information similarity measure used to compare 10242 pixel PRs with 2562 pixel DRRs interpolated to 10242 pixels performed the best. It was also found that the CT data with the smallest slice thickness available should be used. If only CT data with thick slices is available, the CT data should be interpolated to have thinner slices. Five minimization algorithms were implemented and investigated. It was found that the unit vector direction set minimization method can be used to register the simulated PRs robustly and very accurately in a respectable amount of time. Investigations with limited real PRs showed that the behaviour of the registration process is not significantly different than for simulated PRs.

CAPES / Desde os primeiros trabalhos propondo o uso dos prótons para a construção da imagem, a principal vantagem, sobre os raios X, foi esperada como um resultado da propriedade específica do fluxo de próton em diminuir acentuadamente no fim do alcance da partícula. Esta ideia foi declarada, porém não foi checada. No presente trabalho, esta hipótese foi investigada usando simulação Monte Carlo, com o auxílio do software SRIM-2008, para o caso de um detector que registra pequena parte da energia de saída do próton (detector fino). Primeiramente, foi determinada a espessura do detector para a investigação da perda de energia dos prótons em um objeto de água com 20 cm. Foi estudada a dose absorvida necessária para distinguir dois objetos de água com espessura de 20 cm e 20,1 cm, como função da energia inicial. O resultado foi comparado com os dados obtidos por um detector grosso, que registra energia total de saída. A investigação realizada mostrou que a ideia principal de se trabalhar no fim de alcance dos prótons para a construção da imagem, não é correta quando se utiliza detector fino bem como detector grosso. Em geral, os sistemas de detecção, baseados em medidas de energia total de saída, são preferíveis àqueles que se baseiam em detectores finos. / Since the earliest works proposing the use of protons for imaging, the main advantage of protons over X-rays was expected to be a result of the specific property of the proton flux dropping off very steeply at the end of the particle range. This idea was declared but was not checked. In the present work, this assumption was investigated using the Monte Carlo simulation, with the help of SRIM-2008 software, for the case of a detector that registers only a small part of the proton exit energy (thin detector). First, a thickness of such detector was determined for the investigated water object of 20 cm. Then, it was studied the minimum dose absorbed by an object that is necessary to distinguish two water objects with the thicknesses of 20 cm and 20.1 cm as a function of the initial energy. The results were compared with the case of thick detector that registers the total exit energy. The carried out investigation shows that the principal idea of proton imaging to work near the end of the proton range is not correct in the case of thin detector as well as for thick one. In general, detector systems based on the measurement of the total exit energy are preferable to systems based on thin detectors.

CAPES / Desde os primeiros trabalhos propondo o uso dos prótons para a construção da imagem, a principal vantagem, sobre os raios X, foi esperada como um resultado da propriedade específica do fluxo de próton em diminuir acentuadamente no fim do alcance da partícula. Esta ideia foi declarada, porém não foi checada. No presente trabalho, esta hipótese foi investigada usando simulação Monte Carlo, com o auxílio do software SRIM-2008, para o caso de um detector que registra pequena parte da energia de saída do próton (detector fino). Primeiramente, foi determinada a espessura do detector para a investigação da perda de energia dos prótons em um objeto de água com 20 cm. Foi estudada a dose absorvida necessária para distinguir dois objetos de água com espessura de 20 cm e 20,1 cm, como função da energia inicial. O resultado foi comparado com os dados obtidos por um detector grosso, que registra energia total de saída. A investigação realizada mostrou que a ideia principal de se trabalhar no fim de alcance dos prótons para a construção da imagem, não é correta quando se utiliza detector fino bem como detector grosso. Em geral, os sistemas de detecção, baseados em medidas de energia total de saída, são preferíveis àqueles que se baseiam em detectores finos. / Since the earliest works proposing the use of protons for imaging, the main advantage of protons over X-rays was expected to be a result of the specific property of the proton flux dropping off very steeply at the end of the particle range. This idea was declared but was not checked. In the present work, this assumption was investigated using the Monte Carlo simulation, with the help of SRIM-2008 software, for the case of a detector that registers only a small part of the proton exit energy (thin detector). First, a thickness of such detector was determined for the investigated water object of 20 cm. Then, it was studied the minimum dose absorbed by an object that is necessary to distinguish two water objects with the thicknesses of 20 cm and 20.1 cm as a function of the initial energy. The results were compared with the case of thick detector that registers the total exit energy. The carried out investigation shows that the principal idea of proton imaging to work near the end of the proton range is not correct in the case of thin detector as well as for thick one. In general, detector systems based on the measurement of the total exit energy are preferable to systems based on thin detectors.

In a growing number of cutting edge centres around the world, radiotherapy treatments delivered by beams of protons and carbon ions offer the opportunity to target tumours with unprecedented conformality. But a sharper dose distribution increases the need for efficient quality control. Treatments are still affected by uncertainties on the penetration depth of the beam within the patient, requiring medical physicists to add safety margins. To reduce these margins and deliver safer treatments, different projects investigate real time range control by imaging prompt gammas emitted along the proton or carbon ion tracks in the patient.<p><p>This thesis reports on the feasibility, development and test of a new type of prompt gamma camera for proton therapy. This concept uses a knife-edge slit collimator to obtain a 1-dimensional projection of the beam path on a gamma camera. It was optimized, using the Monte Carlo code MCNPX version 2.5.0, to select high energy photons correlated with the beam range and detect them with both high counting statistics and sufficient spatial resolution for use in clinical routine. To validate the Monte Carlo model, spectrometry measurements of secondary particles emitted by a PMMA target during proton irradiation at 160 MeV were realised. An excellent agreement with the simulations was observed when using subtraction methods to isolate the gammas in direct incidence. A first prototype slit camera using the HiCam gamma detector was consequently prepared and tested successfully at 100 and 160 MeV beam energies. If we neglect electronic dead times and rejection of detected events, the current solution with its collimator at 15 cm from beam axis can achieve a 1-2 mm standard deviation on range estimation in a homogeneous PMMA target for numbers of protons that correspond to doses in water at Bragg peak as low as 15 cGy at 100 MeV and 25 cGy at 160 MeV assuming pencil beams with a Gaussian profile of 5 mm sigma at target entrance.<p><p>This thesis also investigates the applicability of the slit camera for carbon ion therapy. On the basis of Monte Carlo simulations with the code MCNPX version 2.7.E, this type of camera appears not to be able to identify the beam range with the required sensitivity. The feasibility of prompt gamma imaging itself seems questionable at high beam energies given the weak correlation of secondaries leaving the patient.<p><p>This work consequently concludes to the relevance of the slit camera approach for real time range monitoring in proton therapy, but not in carbon ion therapy. / Doctorat en Sciences de l'ingénieur / info:eu-repo/semantics/nonPublished

The purpose of this project is to improve the existing version of the Sequential Alignment and Position Verification System (SAPVS) for functional proton radiosurgery and to evaluate its performance after improvement .

Thesis (MSc (Radiography))--Cape Peninsula University of Technology, 2018 / Background: Breast cancer is one of the most commonly diagnosed among woman in South Africa, and a more resilient effort should be focused on treatment improvements. Worldwide, proton therapy is increasingly used as a radiation treatment alternative to photon therapy for breast cancer, mostly to decrease the risk for radiation-induced cardiovascular toxicity. This in vitro study aims to determine a better understanding of the radiosensitivity of both tumour and normal breast cell lines to clinical proton irradiation. In addition, we propose to investigate whether the increase in linear energy transfer (LET) towards the distal part of the proton beam results in an increase in relative biological effectiveness (RBE) for both cell lines. Methods: Malignant (MCF-7) and non-malignant (MCF-10A) breast cells were irradiated at different water equivalent depths in a 200 MeV proton beam at NRF iThemba LABS using a custom-made Perspex phantom: the entrance plateau, 3 points on the Bragg peak, the D80% and the D40%. A cytokinesis-block Micronucleus (CBMN) assay was performed and Micronuclei (MNi) were manually counted in binucleated cells (BNCs) using fluorescent microscopy. Reference dosimetry was carried out with a Markus chamber and irradiations were performed with a clinical proton beam generated at NRF iThemba LABS that was degraded to a R50 (half-value depths) range of 120 mm, with a field size of 10 cm x 10 cm and a 50 mm SOBP. The phantom could be adjusted to accommodate different perspex plates depending on the depth required within the proton beam. Cells were then exposed to 0.5, 1.0, 2.0, 3.0 and 4.0 Gy doses for each cell line independently and for each dose point. Results and Discussion: For the CBMN results, a program was developed on Matlab platform to calculate the 95% confidence ellipse on the co-variance parameters α and β. These values were determined by fitting the linear quadratic dose response curve to the average number of radiation induced MNi per 1000 BN cells. The ellipse region around a coordinate (the average MN frequency) for both MCF-7 and MCF-10A cells at the plateau region was defined by the mean estimate of the α-value and the β-value that were plotted on the X-axis and Y-axis respectively. The ratio of the two parameters, α/β, is a measure of the impact of fractionation to determine the biological effective dose. In fractionated proton therapy, the MCF10A cells will repair less between two fractions compared to the MCF7 cells. This is not an indication of therapeutic gain from a fractioned treatment protocol. For this reason, the hypofractionated stereotactic treatment protocols that can be applied with protons could be to the befit of the breast cancer patient. The above argument is based only on the radiosensitivity of the two cell lines exposed in the plateau region. Further analysis of the 95% confidence ellipse of both cell lines also showed a clear increase of the alpha value toward the distal portion of the beam and indicates an increase in energy transfer in this region. The gradual increase in α and β parameters with depth for protons for both cells is of clinical importance, since it implicates a non-homogeneous dose within the targeted area and an unwanted high dose behind the targeted area. Distal energy modulation could be investigated especially with larger breast tumours. RBE was calculated as the ratio of the dose at the different positions to the dose at the entrance plateau position (reference) to obtain an equal level of biological effect. A statistically significant difference in radiosensitivity could be observed between malignant and non-malignant cells at all positions (p<0.05). The variation in RBE was between 0.99 to 1.99 and 0.92 to 1.6 for the MCF-7 and MCF10A cell respectively. Conclusions: There is a variation in RBE along the depth-dose profile of a clinical proton beam. In addition, there is difference in radiosensitivity between the cancerous cells and the normal breast cells. While this study highlights a variation in sensitivity between cells it could be used by the modelling community to further develop biologically motivated treatment planning for proton therapy.

Thesis (Ph.D.); Submitted to the Univ. of California, Berkeley, CA (US); 24 Nov 2004. / Published through the Information Bridge: DOE Scientific and Technical Information. "UCRL-TH-208645" Allen, M. 11/24/2004. Report is also available in paper and microfiche from NTIS.

Proton therapy is a relatively new treatment modality for cancer, having recently been incorporated into hospitals in the last two decades. Although proton therapy has much higher start up and treatment costs than traditional methods of radiotherapy, it continues to expand in use today. One reason for this is that proton therapy has the advantage of a more precise localization of dose compared to traditional radiotherapy. Other proposed advantages of proton therapy in the treatment of cancer may lead to a faster expanse in its use if proven to be more effective than traditional radiotherapy. Therefore, much research must be done to investigate the possible negative and positive effects of using proton therapy as a treatment modality. In proton therapy, protons do account for the vast majority of dose. However, when protons travel through matter, secondary particles are created by the interactions of protons and matter en route to and within the patient. It is believed that secondary dose can lead to secondary cancer, especially in pediatric cases. Therefore, the focus of this work is determining both primary and secondary dose. In order to develop relevant simulations, the specifications of the treatment room and beam were based off of real-world facilities as closely as possible. Using available data from proton accelerators and clinical facilities, an accurate proton therapy nozzle was designed. Dose calculations were performed by MCNPX using a simple water phantom, and then beam characteristics were investigated to ensure the accuracy of the model. After validation of the beam nozzle, primary and secondary dose values were tabulated and discussed. By demonstrating the method of these calculations, the purpose of this work is to serve as a guide into the relatively recent field of Monte Carlo methods in proton therapy.

Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro / Nessa tese foi feito um estudo preliminar, destinado à elaboração do programa experimental inicial para a primeira instalação da tomografia com prótons (pCT) brasileira por meio de modelagem computacional. A terapia com feixe de prótons é uma forma bastante precisa de tratamento de câncer. Atualmente, o planejamento de tratamento é baseado na tomografia computadorizada com raios X, alternativamente, a tomografia com prótons pode ser usada. Algumas questões importantes, como efeito de escala e a Curva de Calibração (fonte de dados iniciais para planejamento de terapia com prótons), foram estudados neste trabalho. A passagem de prótons com energias iniciais de 19,68MeV; 23MeV; 25MeV; 49,10MeV e 230MeV pelas camadas de materiais variados (água, alumínio, polietileno, ouro) foi simulada usando códigos Monte Carlo populares como SRIM e GEANT4. Os resultados das simulações foram comparados com a previsão teórica (baseada na solução aproximada da equação de transporte de Boltzmann) e com resultados das simulações feitas com outro popular código Monte Carlo MCNPX. Análise comparativa dos resultados das simulações com dados experimentais publicados na literatura científica para alvos grossos e na faixa de energias de prótons usada em medidas em pCT foi feita. Foi observado que apesar de que todos os códigos mostram os resultados parecidos alguns deslocamentos não sistemáticos podem ser observados. Foram feitas observações importantes sobre a precisão dos códigos e uma necessidade em medidas sistemáticas de frenagem de prótons em alvos grossos foi declarada. / In the present work a preliminary research via computer simulations was made in order to elaborate a prior program for the first experimental pCT setup in Brazil. Proton therapy is a high precise form of a cancer treatment. Treatment planning nowadays is performed basing on X ray Computer Tomography data (CT), alternatively the same procedure could be performed using proton Computer Tomography (pCT). Some important questions, as a scale effect and so called Calibration Curve (as a source of primary data for pCT treatment planning) were studied in this work. The 19.68MeV; 23MeV; 25MeV; 49.10MeV e 230MeV protons passage through varied absorbers (water, aluminum, polyethylene, gold) were simulated by such popular Monte Carlo packages as SRIM and GEANT4. The simulation results were compared with a theoretic prevision based on approximate solution of the Boltzmann transport equation and with simulation results of the other popular Monte Carlo code MCNPX. The comparative analysis of the simulations results with the experimental data published in scientific literature for thick absorbers and within the energy range used in the pCT measurements was made. It was noted in spite of the fact that all codes showed similar results some nonsystematic displacements can be observed. Some important observations about the codes precision were made and a necessity of the systematic measurements of the proton stopping power in thick absorbers was declared.