Unsicherheiten in der Reichweitevorhersage limitieren wesentlich das Ausnutzen der Vorteile von Protonentherapie gegenüber konventioneller Strahlentherapie. Die Verwendung von Zwei-Spektren-Computertomographie (DECT) zur direkten Vorhersage des Bremsvermögen (DirectSPR) ermöglicht eine relevante Verbesserung der Reichweitevorhersage gegenüber der üblicherweise verwendeten Ein-Spektren-Computertomographie (SECT). Im Rahmen dieser Dissertation wurde die Variation in der Reichweitevorhersage zwischen 17 europäischen Partikeltherapiezentren experimentell verglichen. Die Genauigkeit der Reichweitevorhersage bei Verwendung einer DirectSPR-Implementierung wurde umfassend quantifiziert und die Implementierung in die klinische Routine integriert. Dies führte zu einer Reduzierung des klinischen Sicherheitssaum um ca. 35% für die Behandlung von quasistatischen Tumoren in Kopf und Becken und damit einer Schonung des Normalgewebes sowie der das Zielgebiet umgebenden Risikoorgane. Darüber hinaus wurde die DirectSPR-Implementierung zur Bestimmung von Gewebeparametern sowie deren Variabilität für zehn Organe im Kopf und Becken in einer Patienkohorte genutzt. Die vorgestellten Ergebnisse etablieren DECT weiter als zukünftiges Standard-Bildgebungsverfahren in der Partikeltherapie.:1. Introduction 2. Proton therapy 2.1. Physical principles of proton therapy 2.2. Treatment with protons 2.3. Accuracy in proton therapy 3. CT Imaging for proton therapy 3.1. Principles of CT imaging 3.2. CT-based range prediction 3.3. Investigated phantoms and materials 3.4. DECT scan acquisition 3.5. Determination of proton stopping power for reference materials 4. Accuracy of stopping-power prediction in European proton centres 4.1. Study design 4.2. Experimental setup and analysis 4.3. Results 4.4. Discussion of determined deviations 4.5. Conclusion and outlook 4.6. Establishment of guidelines for HLUT calibration 5. Range uncertainties in DirectSPR-based treatment planning 5.1. Clinical implementation of DirectSPR 5.2. Uncertainty quantification 5.3. Resulting uncertainties in SPR prediction 5.4. Experimental validation 5.5. Dosimetric effect of range uncertainty reduction 5.6. Discussion 6. In-vivo tissue characterisation using DirectSPR 6.1. Tissue parameter determination by Woodard and White 6.2. Data preparation and analysis 6.3. Determined tissue parameters and variations 6.4. Discussion 7. The future of image-based range prediction 7.1. Particle imaging 7.2. Creation of synthetic CT images 7.3. Photon-counting computed tomography 8. Summary 9. Zusammenfassung A. Supplement A.1. Investigated materials A.2. EPTN study: Individual results A.3. DirectSPR validation results / Imaging-related range uncertainties effectively limit the full exploitation of the benefits proton therapy offers with respect to conventional photon radiotherapy. The use of dual-energy computed tomography (DECT) for direct stopping-power prediction (DirectSPR) was determined to provide relevant improvements in range prediction over commonly used singleenergy CT (SECT). Within this thesis, the variation in range prediction accuracy between 17 European particle treatment centres were experimentally quantified to determine the current status quo in the community. The overall range uncertainty when using a DirectSPR implementation in treatment planning was comprehensively quantified and the implementation integrated into the clinical workflow. This led to a reduction of clinical safety margins by about 35% for the treatment of quasi-static tumours in the head and pelvis, effectively reducing the dose to surrounding healthy tissue and organs at risk. The DirectSPR implementation was furthermore utilised to assess tissue parameters and their inter- and intra-patient variability for ten organs in the head and pelvis from a cohort of patients. The presented results further establish DirectSPR as the future standard imaging modality in particle therapy.:1. Introduction 2. Proton therapy 2.1. Physical principles of proton therapy 2.2. Treatment with protons 2.3. Accuracy in proton therapy 3. CT Imaging for proton therapy 3.1. Principles of CT imaging 3.2. CT-based range prediction 3.3. Investigated phantoms and materials 3.4. DECT scan acquisition 3.5. Determination of proton stopping power for reference materials 4. Accuracy of stopping-power prediction in European proton centres 4.1. Study design 4.2. Experimental setup and analysis 4.3. Results 4.4. Discussion of determined deviations 4.5. Conclusion and outlook 4.6. Establishment of guidelines for HLUT calibration 5. Range uncertainties in DirectSPR-based treatment planning 5.1. Clinical implementation of DirectSPR 5.2. Uncertainty quantification 5.3. Resulting uncertainties in SPR prediction 5.4. Experimental validation 5.5. Dosimetric effect of range uncertainty reduction 5.6. Discussion 6. In-vivo tissue characterisation using DirectSPR 6.1. Tissue parameter determination by Woodard and White 6.2. Data preparation and analysis 6.3. Determined tissue parameters and variations 6.4. Discussion 7. The future of image-based range prediction 7.1. Particle imaging 7.2. Creation of synthetic CT images 7.3. Photon-counting computed tomography 8. Summary 9. Zusammenfassung A. Supplement A.1. Investigated materials A.2. EPTN study: Individual results A.3. DirectSPR validation results

No description available.

Proton radiotherapy is a cancer treatment which has the potential to offer greater cure rates and/or fewer serious side effects than conventional radiotherapy. Its availability in the UK is currently limited to a single low-energy fixed beamline for the treatment of ocular tumours, but a number of facilities designed to treat deep-seated tumours are in development. This thesis focusses on the quantitative use of x-ray computed tomography (CT) images in planning proton radiotherapy treatments. It arrives at several recommendations that can be used to inform clinical protocols for the acquisition of planning scans, and their subsequent use in treatment planning systems. The primary tool developed is a software CT scanner, which simulates images of an anthropomorphic virtual phantom, informed by measurements taken on a clinical scanner. The software is used to investigate the accuracy of the stoichiometric method for calibrating CT image pixel values to proton stopping power, with particular attention paid to the impact of beam hardening and photon starvation artefacts. The strength of the method adopted is in allowing comparison between CT-estimated and exactly-calculated proton stopping powers derived from the same physical data (specified in the phantom), leading to results that are difficult to obtain otherwise. A number of variations of the stoichiometric method are examined, identifying the best-performing calibration phantom and CT tube voltage (kVp). Improvements in accuracy are observed when using a second-pass beam hardening correction algorithm. Also presented is a method for identifying the proton paths where stopping power uncertainties are likely to be greatest. Estimates of the proton range uncertainties caused by CT artefacts and calibration errors are obtained for a range of realistic clinical scenarios. The current practice of including planning margins equivalent to 3.5% of the range is found to ensure coverage in all but the very worst of cases. Results herein suggest margins could be reduced to <2% if the best-performing protocol is followed; however, an analysis specific to the CT scanner and treatment site in question should be carried out before such a change is made in the clinic.

Background: The irradiation of cancer patients with charged particles, mainly protons and carbon ions, has become an established method for the treatment of specific types of tumors. In comparison with the use of X-rays or gamma-rays, particle therapy has the advantage that the dose distribution in the patient can be precisely controlled. Tissue or organs lying near the tumor will be spared. A verification of the treatment plan with the actual dose deposition by means of a measurement can be done through range assessment of the particle beam. For this purpose, prompt gamma-rays are detected, which are emitted by the affected target volume during irradiation. Motivation: The detection of prompt gamma-rays is a task related to radiation detection and measurement. Nuclear applications in medicine can be found in particular for in vivo diagnosis. In that respect the spatially resolved measurement of gamma-rays is an essential technique for nuclear imaging, however, technical requirements of radiation measurement during particle therapy are much more challenging than those of classical applications. For this purpose, appropriate instruments beyond the state-of-the-art need to be developed and tested for detecting prompt gamma-rays. Hence the success of a method for range assessment of particle beams is largely determined by the implementation of electronics. In practice, this means that a suitable detector material with adapted readout electronics, signal and information processing, and data interface must be utilized to solve the challenges. Thus, the parameters of the system (e.g. segmentation, time or energy resolution) can be optimized depending on the method (e.g. slit camera, time-of-flight measurement or Compton camera). Regardless of the method, the detector system must have a high count rate capability and a large measuring range (>7 MeV). For a subsequent evaluation of a suitable method for imaging, the mentioned parameters may not be restricted by the electronics. Digital signal processing is predestined for multipurpose tasks, and, in terms of the demands made, the performance of such an implementation has to be determined. Materials and methods: In this study, the instrumentation of a detector system for prompt gamma-rays emitted during particle therapy is limited to the use of a cadmium zinc telluride (CdZnTe, CZT) semiconductor detector. The detector crystal is divided into an 8x8 pixel array by segmented electrodes. Analog and digital signal processing are exemplarily tested with this type of detector and aims for application of a Compton camera to range assessment. The electronics are implemented with commercial off-the-shelf (COTS) components. If applicable, functional units of the detector system were digitalized and implemented in a field-programmable gate array (FPGA). An efficient implementation of the algorithms in terms of timing and logic utilization is fundamental to the design of digital circuits. The measurement system is characterized with radioactive sources to determine the measurement dynamic range and resolution. Finally, the performance is examined in terms of the requirements of particle therapy with experiments at particle accelerators. Results: A detector system based on a CZT pixel detector has been developed and tested. Although the use of an application-specific integrated circuit is convenient, this approach was rejected because there was no circuit available which met the requirements. Instead, a multichannel, compact, and low-noise analog amplifier circuit with COTS components has been implemented. Finally, the 65 information channels of a detector are digitized, processed and visualized. An advanced digital signal processing transforms the traditional approaches of nuclear electronics in algorithms and digital filter structures for an FPGA. With regard to the characteristic signals (e.g. varying rise times, depth-dependent energy measurement) of a CZT pixel detector, it could be shown that digital pulse processing results in a very good energy resolution (~2% FWHM at 511 keV), as well as permits a time measurement in the range of some tens of nanoseconds. Furthermore, the experimental results have shown that the dynamic range of the detector system could be significantly improved compared to the existing prototype of the Compton camera (~10 keV..7 MeV). Even count rates of ~100 kcps in a high-energy beam could be ultimately processed with the CZT pixel detector. But this is merely a limit of the detector due to its volume, and not related to electronics. In addition, the versatility of digital signal processing has been demonstrated with other detector materials (e.g. CeBr3). With foresight on high data throughput in a distributed data acquisition from multiple detectors, a Gigabit Ethernet link has been implemented as data interface. Conclusions: To fully exploit the capabilities of a CZT pixel detector, a digital signal processing is absolutely necessary. A decisive advantage of the digital approach is the ease of use in a multichannel system. Thus with digitalization, a necessary step has been done to master the complexity of a Compton camera. Furthermore, the benchmark of technology shows that a CZT pixel detector withstands the requirements of measuring prompt gamma-rays during particle therapy. The previously used orthogonal strip detector must be replaced by the pixel detector in favor of increased efficiency and improved energy resolution. With the integration of the developed digital detector system into a Compton camera, it must be ultimately proven whether this method is applicable for range assessment in particle therapy. Even if another method is more convenient in a clinical environment due to practical considerations, the detector system of that method may benefit from the shown instrumentation of a digital signal processing system for nuclear applications. / Hintergrund: Die Bestrahlung von Krebspatienten mit geladenen Teilchen, vor allem Protonen oder Kohlenstoffionen, ist mittlerweile eine etablierte Methode zur Behandlung von speziellen Tumorarten. Im Vergleich mit der Anwendung von Röntgen- oder Gammastrahlen hat die Teilchentherapie den Vorteil, dass die Dosisverteilung im Patienten präziser gesteuert werden kann. Dadurch werden um den Tumor liegendes Gewebe oder Organe geschont. Die messtechnische Verifikation des Bestrahlungsplans mit der tatsächlichen Dosisdeposition kann über eine Reichweitenkontrolle des Teilchenstrahls erfolgen. Für diesen Zweck werden prompte Gammastrahlen detektiert, die während der Bestrahlung vom getroffenen Zielvolumen emittiert werden. Fragestellung: Die Detektion von prompten Gammastrahlen ist eine Aufgabenstellung der Strahlenmesstechnik. Strahlenanwendungen in der Medizintechnik finden sich insbesondere in der in-vivo Diagnostik. Dabei ist die räumlich aufgelöste Messung von Gammastrahlen bereits zentraler Bestandteil der nuklearmedizinischen Bildgebung, jedoch sind die technischen Anforderungen der Strahlendetektion während der Teilchentherapie im Vergleich mit klassischen Anwendungen weitaus anspruchsvoller. Über den Stand der Technik hinaus müssen für diesen Zweck geeignete Instrumente zur Erfassung der prompten Gammastrahlen entwickelt und erprobt werden. Die elektrotechnische Realisierung bestimmt maßgeblich den Erfolg eines Verfahrens zur Reichweitenkontrolle von Teilchenstrahlen. Konkret bedeutet dies, dass ein geeignetes Detektormaterial mit angepasster Ausleseelektronik, Signal- und Informationsverarbeitung sowie Datenschnittstelle zur Problemlösung eingesetzt werden muss. Damit können die Parameter des Systems (z. B. Segmentierung, Zeit- oder Energieauflösung) in Abhängigkeit der Methode (z.B. Schlitzkamera, Flugzeitmessung oder Compton-Kamera) optimiert werden. Unabhängig vom Verfahren muss das Detektorsystem eine hohe Ratenfestigkeit und einen großen Messbereich (>7 MeV) besitzen. Für die anschließende Evaluierung eines geeigneten Verfahrens zur Bildgebung dürfen die genannten Parameter durch die Elektronik nicht eingeschränkt werden. Eine digitale Signalverarbeitung ist für universelle Aufgaben prädestiniert und die Leistungsfähigkeit einer solchen Implementierung soll hinsichtlich der gestellten Anforderungen bestimmt werden. Material und Methode: Die Instrumentierung eines Detektorsystems für prompte Gammastrahlen beschränkt sich in dieser Arbeit auf die Anwendung eines Cadmiumzinktellurid (CdZnTe, CZT) Halbleiterdetektors. Der Detektorkristall ist durch segmentierte Elektroden in ein 8x8 Pixelarray geteilt. Die analoge und digitale Signalverarbeitung wird beispielhaft mit diesem Detektortyp erprobt und zielt auf die Anwendung zur Reichweitenkontrolle mit einer Compton-Kamera. Die Elektronik wird mit seriengefertigten integrierten Schaltkreisen umgesetzt. Soweit möglich, werden die Funktionseinheiten des Detektorsystems digitalisiert und in einem field-programmable gate array (FPGA) implementiert. Eine effiziente Umsetzung der Algorithmen in Bezug auf Zeitverhalten und Logikverbrauch ist grundlegend für den Entwurf der digitalen Schaltungen. Das Messsystem wird mit radioaktiven Prüfstrahlern hinsichtlich Messbereichsdynamik und Auflösung charakterisiert. Schließlich wird die Leistungsfähigkeit hinsichtlich der Anforderungen der Teilchentherapie mit Experimenten am Teilchenbeschleuniger untersucht. Ergebnisse: Es wurde ein Detektorsystem auf Basis von CZT Pixeldetektoren entwickelt und erprobt. Obwohl der Einsatz einer anwendungsspezifischen integrierten Schaltung zweckmäßig wäre, wurde dieser Ansatz zurückgewiesen, da kein verfügbarer Schaltkreis die Anforderungen erfüllte. Stattdessen wurde eine vielkanalige, kompakte und rauscharme analoge Verstärkerschaltung mit seriengefertigten integrierten Schaltkreisen aufgebaut. Letztendlich werden die 65 Informationskanäle eines Detektors digitalisiert, verarbeitet und visualisiert. Eine fortschrittliche digitale Signalverarbeitung überführt die traditionellen Ansätze der Nuklearelektronik in Algorithmen und digitale Filterstrukturen für einen FPGA. Es konnte gezeigt werden, dass die digitale Pulsverarbeitung in Bezug auf die charakteristischen Signale (u.a. variierende Anstiegszeiten, tiefenabhängige Energiemessung) eines CZT Pixeldetektors eine sehr gute Energieauflösung (~2% FWHM at 511 keV) sowie eine Zeitmessung im Bereich von einigen 10 ns ermöglicht. Weiterhin haben die experimentellen Ergebnisse gezeigt, dass der Dynamikbereich des Detektorsystems im Vergleich zum bestehenden Prototyp der Compton-Kamera deutlich verbessert werden konnte (~10 keV..7 MeV). Nach allem konnten auch Zählraten von >100 kcps in einem hochenergetischen Strahl mit dem CZT Pixeldetektor verarbeitet werden. Dies stellt aber lediglich eine Begrenzung des Detektors aufgrund seines Volumens, nicht jedoch der Elektronik, dar. Zudem wurde die Vielseitigkeit der digitalen Signalverarbeitung auch mit anderen Detektormaterialen (u.a. CeBr3) demonstriert. Mit Voraussicht auf einen hohen Datendurchsatz in einer verteilten Datenerfassung von mehreren Detektoren, wurde als Datenschnittstelle eine Gigabit Ethernet Verbindung implementiert. Schlussfolgerung: Um die Leistungsfähigkeit eines CZT Pixeldetektors vollständig auszunutzen, ist eine digitale Signalverarbeitung zwingend notwendig. Ein entscheidender Vorteil des digitalen Ansatzes ist die einfache Handhabbarkeit in einem vielkanaligen System. Mit der Digitalisierung wurde ein notwendiger Schritt getan, um die Komplexität einer Compton-Kamera beherrschbar zu machen. Weiterhin zeigt die Technologiebewertung, dass ein CZT Pixeldetektor den Anforderungen der Teilchentherapie für die Messung prompter Gammastrahlen stand hält. Der bisher eingesetzte Streifendetektor muss zugunsten einer gesteigerten Effizienz und verbesserter Energieauflösung durch den Pixeldetektor ersetzt werden. Mit der Integration des entwickelten digitalen Detektorsystems in eine Compton-Kamera muss abschließend geprüft werden, ob dieses Verfahren für die Reichweitenkontrolle in der Teilchentherapie anwendbar ist. Auch wenn sich herausstellt, dass ein anderes Verfahren unter klinischen Bedingungen praktikabler ist, so kann auch dieses Detektorsystem von der gezeigten Instrumentierung eines digitalen Signalverarbeitungssystems profitieren.

En proton thérapie, la technique de balayage, permet de traiter efficacement le patient vis à vis de l'irradiation de la tumeur et la protection des tissus sains. Ces bénéfices dosimétriques peuvent cependant être grandement dégradés par les mouvements intra-fraction. Par conséquent, l'étude de méthodes d'atténuation ou d'adaptation est nécessaire. C'est pour cela, que nous avons développé un logiciel ”open-source” de calcul et d'évaluation de dose en 4D, MSPT (Motion Simulator for Proton Therapy), pour la technique de balayage. Son but est de mettre en avant l'impact des mouvements intra-fraction en calculant la répartition de dose dans le patient. En outre, l'utilisation de MSPT nous a permis de mettre au point et de proposer une nouvelle méthode d'atténuation du mouvement basée sur l'ajustement du poids du faisceau quand celui-ci balaye la tumeur. En photon thérapie, un enjeu principal pour les traitements délivrés à l'aide de collimateurs multi-lames (MLC) consiste à trouver un ensemble de configurations du MLC permettant d'irradier correctement la tumeur. L'efficacité d'un tel ensemble se mesure par le total beam-on time et le total setup time. Dans notre étude, nous nous intéressons à la minimisation de ces critères, d'un point de vue algorithmique, pour de nouvelles technologies de MLC: le MLC rotatif et le MLC à double couche. De plus, nous proposons un algorithme d'approximation pour trouver un ensemble de configurations minimisant le total beam-on time pour le MLC rotatif / In proton therapy, the delivery method named spot scanning, can provide a particularly efficient treatment in terms of tumor coverage and healthy tissues protection. The dosimetric benefits of proton therapy may be greatly degraded due to intra-fraction motions. Hence, the study of mitigation or adaptive methods is necessary. For this purpose, we developed an open-source 4D dose computation and evaluation software, MSPT (Motion Simulator for Proton Therapy), for the spot-scanning delivery technique. It aims at highlighting the impact of intra-fraction motions during a treatment delivery by computing the dose distribution in the moving patient. In addition, the use of MSPT allowed us to develop and propose a new motion mitigation strategy based on the adjustment of the beam's weight when the proton beam is scanning across the tumor. In photon therapy, a main concern for deliveries using a multileaf collimator (MLC) relies on finding a series of MLC configurations to deliver properly the treatment. The efficiency of such series is measured by the total beam-on time and the total setup time. In our work, we study the minimization of these efficiency criteria from an algorithmic point of view, for new variants of MLCs: the rotating MLC and the dual-layer MLC. In addition, we propose an approximation algorithm to find a series of configurations that minimizes the total beam-on time for the rotating MLC

The treatment plan for radiation therapy with protons is based on images from a computed tomography (CT) scanner. This is problematic since the photons in the x-ray beam from the CT scanner and the protons are affected differently by the tissue in the patient, which introduce an uncertainty in the track length of the protons. The hypothesis of this study is that a new generation of CT scanners (DECT), with the capacity to simultaneously scan the patient with two photon spectra of different mean energy, will improve the tissue characterisation and which in turn reduce the uncertainty in the track length of the protons. In this study, the accuracy and precision of a DECT-based method from the literature is compared to the conventional calibration method used today at the University clinics in Sweden to relate the attenuation of the photon beam to the slowing down of the protons. The methods are tested on CT images of a phantom, a plastic body containing tissue equivalent plastic inserts of known elemental composition. The results turned out to be inconclusive as there were large uncertainties in the measurements. The method has potential, as has been shown in the literature, but there are many questions that need to be answered before the method is ready to be implemented at the clinic. / En proton som färdas genom människokroppen deponerar endast en liten del av sin energi längs vägen innan den plötsligt deponerar allt i slutet på dess bana. Hur lång dess bana är beror på protonens ursprungliga energi och den atomära sammansättningen hos vävnaden den passerar igenom. Om sammansättningen är känd går det genom att justera den initiala energin bestämma banlängden. Denna egenskap gör protonen väldigt attraktiv för strålterpi, då det innbär möjligheten att behandla med hög precision samt bespara frisk vävnad onödig dos. Strålterapi med protoner planeras idag med bilder från en skiktröntgen (CT) som underlag. Ett problem med det är att röntgenstrålarna från CT-skannern påverkas annorlunda än protonerna av vävnaden, vilket introducerar en osäkerhet i protonernas banlängd. Hypotesen i denna studie är att en ny generation av CT-scanner (DECT), med möjlighet att simultant skanna patienten med två fotonspektran av olika medelenergi, på ett bättre sätt ska kunna bestämma den atomära sammansättningen för vävnaden och därmed reducera osäkerheten i protonernas banlängd. Noggrannhet och precision för en DECT-baserad metod från litteraturen jämförs med den SECT-baserade kalibreringsmetoden, som idag används på Universitetssjukhusen i Sverige för att relatera fotonstrålens dämpning i vävnaden till protonernas inbromsning. Metoderna testas på CT bilder av ett fantom, en plastkropp innehållandes olika cylindrar av vävnadsekvivalent plast med känd atomär sammansättning. Resultatet av den här studien är inte starkt nog för att bevisa hypotesen för studien. Det insamlade bildmaterialet innehåller höga brusnivåer jämfört med de som rapporteras i literaturen. Brusnivåer är så höga att det mesta av resultatet inte kan anses som statistiskt signifikant. Det är dessutom svårt att göra en direkt jämförelse av prestanda med befintlig teori för vävnadskaraktärisering, då bildmaterialet från de CT skanners som jämfördes är av olika typer. De resultat som publicerats i litteraturen visar att den DECT-baserade metoden har potential, men den här studien gör tydligt att det fortfarande finns frågor som måste besvaras innan metoden är redo att implementeras kliniskt.

Evidence that radiation-related cardiovascular disease and second primary cancers can occur in cancer survivors following radiation therapy (RT) has emerged from several independent sources. Cardiotoxicity and second cancers are of particular concern for patients with good prognosis, such as those with Hodgkin lymphoma (HL). HL patients are among the youngest to receive RT, which means that those who are cured of their cancer have decades-long natural life-expectancies during which treatment-related long-term toxicities may cause years of excess morbidity or premature mortality. A considerable amount of research has been conducted to investigate the risk of radiation-related cardiotoxicity and second cancers. However, there are still substantial gaps in knowledge. It is therefore important to improve our understanding regarding these risks and develop treatment approaches and survivorship care to minimise their impact on patients' quality of life. In this thesis, I have investigated the risk of congestive heart failure (CHF) in a cohort of 2619 HL survivors and presented, for the first time, dose-response relationships for risk of CHF versus cardiac radiation doses. I also validated the radiation dosimetry method used to estimate the cardiac doses in this study as well as for other reconstruction methods, versus a gold standard based on the patients' own computed tomography scans. Additionally, I investigated what effect the dose reconstruction errors had on the dose-response relationships. I then focused on modern RT methods and specifically on proton RT. Based on published dose-response relationships (including that developed in this thesis) I predicted cardiovascular and second cancer risks for patients treated with advanced RT. This thesis has provided new knowledge in the study of late effects in HL patients who were treated decades ago as well as for patients treated more recently with advanced RT methods. The results here can be used to facilitate progress towards personalised RT in terms of choosing the appropriate RT method by integrating individualised risk prediction in advanced RT treatment planning. The research here provides the basis for further work towards evidence-based case selection for HL patients for the first NHS proton therapy centres in the UK, opening in 2018-2021.

Dual-energy computed tomography (DECT) has shown great potential in the reduction of uncertainties of proton ranges and low energy photon cross section estimation used in radiation therapy planning. The work presented herein investigated three contributions for advancing DECT applications. 1) A linear and separable two-parameter DECT, the basis vector model (BVM) was used to estimate proton stopping power. Compared to other nonlinear two-parameter models in the literature, the BVM model shows a comparable accuracy achieved for typical human tissues. This model outperforms other nonlinear models in estimations of linear attenuation coefficients. This is the first study to clearly illustrate the advantages of linear model not only in accurately mapping radiological quantities for radiation therapy, but also in providing a unique model for accurate linear forward projection modelling, which is needed by the statistical iterative reconstruction (SIR) and other advanced DECT reconstruction algorithms. 2) Accurate DECT requires knowledge of x-ray beam properties. Using the Birch-Marshall1 model and beam hardening correction coefficients encoded in a CT scanner’s sinogram header files, an efficient and accurate way to estimate the x-ray spectrum is proposed. The merits of the proposed technique lie in requiring no physical transmission measurement after a one-time calibration against an independently measured spectrum. This technique can also be used in monitoring the aging of x-ray CT tubes. 3) An iterative filtered back projection with anatomical constraint (iFBP-AC) algorithm was also implemented on a digital phantom to evaluate its ability in mitigating beam hardening effects and supporting accurate material decomposition for in vivo imaging of photon cross section and proton stopping power. Compared to iFBP without constraints, both algorithms demonstrate high efficiency of convergence. For an idealized digital phantom, similar accuracy was observed under a noiseless situation. With clinically achievable noise level added to the sinograms, iFBP-AC greatly outperforms iFBP in prediction of photon linear attenuation at low energy, i.e., 28 keV. The estimated mean errors of iFBP and iFBP-AC for cortical bone are 1% and 0.7%, respectively; the standard deviations are 0.6% and 5%, respectively. The achieved accuracy of iFBP-AC shows robustness versus contrast level. Similar mean errors are maintained for muscle tissue. The standard deviation achieved by iFBP-AC is 1.2%. In contrast, the standard deviation yielded by iFBP is about 20.2%. The algorithm of iFBP-AC shows potential application of quantitative measurement of DECT. The contributions in this thesis aim to improve the clinical performance of DECT.

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.

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