Virtual clinical trials in medical imaging: a review

The accelerating complexity and variety of medical imaging devices and methods have outpaced the ability to evaluate and optimize their design and clinical use. This is a significant and increasing challenge for both scientific investigations and clinical applications. Evaluations would ideally be done using clinical imaging trials. These experiments, however, are often not practical due to ethical limitations, expense, time requirements, or lack of ground truth. Virtual clinical trials (VCTs) (also known as in silico imaging trials or virtual imaging trials) offer an alternative means to efficiently evaluate medical imaging technologies virtually. They do so by simulating the patients, imaging systems, and interpreters. The field of VCTs has been constantly advanced over the past decades in multiple areas. We summarize the major developments and current status of the field of VCTs in medical imaging. We review the core components of a VCT: computational phantoms, simulators of different imaging modalities, and interpretation models. We also highlight some of the applications of VCTs across various imaging modalities

Development of X-ray phase-contrast imaging techniques for medical diagnostics

The X-Ray phase-contrast techniques are innovative imaging methods allowing overtaking the limitations of classic radiology. In addition to the differential X-ray absorption on which standard radiology relies, in phase-contrast imaging the contrast is given by the effects of the refraction of X-rays inside the tissues. The combination of phase-contrast with quantitative computer tomography (CT) allows for a highly accurate reconstruction of the tissues’ index of refraction. Thanks to the high sensitivity of the method, tomographic images can be obtained at clinically compatible dose. For all these reasons phase-contrast imaging is a very promising approach, which can potentially revolutionize diagnostic X-Ray imaging. Several techniques are classified under the name of X-Ray phase-contrast imaging. This Thesis focused on the so-called analyzer-based imaging (ABI) method. ABI uses a perfect crystal, placed between the sample and the detector, to visualize the phase effects occurred within the sample. The quantitative reconstruction of the refraction index from CT data is not trivial and before this Thesis work it was documented only for small size objects. This Thesis has focused on two main scientific problems: (1) the development of theoretical and calculation strategies to determine the quantitative map of the refraction index of large biological tissues/organs (>10 cm) using the ABI technique; and (2) the preparation of accurate and efficient tools to estimate and simulate the dose deposited in CT imaging of large samples. For the determination of the refraction index, two CT geometries were considered and studied: the out-of-plane and the in-plane configurations. The first one, the most used in the works reported in the literature, foresees that the rotation axis of the sample occurs in a plane parallel to that of the sensitivity of the analyzer crystal; while, in the second CT geometry, the rotation axis is perpendicular to that plane. The theoretical study, technical design and experimental implementation of the in-plane geometry have been main tasks of this Thesis. A first experiment has been performed in order to compare the results obtained with in-plane quantitative phase contrast CT with the absorption-based CT ones. An improved accuracy and a better agreement with the theoretical density values have been obtained by exploiting the refraction effect while keeping the dose to sample low. A second campaign of experiments has been performed on large human breasts to investigate the efficiency of the in-plane and out-of-plane CT geometries and the performances of the associated image reconstruction procedures. The same experimental conditions were also studied by numerical simulations and the results were compared. This analysis shows that the in-plane geometry allows producing more accurate quantitative three dimensional maps of the index of refraction, while the out-of-plane case is preferable for qualitative investigations. A study for developing advanced procedures for improving the quality of the obtained CT images has been also conducted. As a result, a two-step procedure has been tested and identified: first the noise level of the experimental images is reduced by applying a wavelet decomposition algorithm and then a deconvolution procedure. The obtained images show an enhanced sharpness of the interfaces and of the object edges and high signal to noise ratio values are preserved. The second problem of this Thesis was to find strategies to calculate, in a fast way, the delivered dose in CT imaging of complex biological samples. For this purpose an acceleration method to speed-up the convergence of Monte Carlo simulations based on the Track Length Estimator method has been computed and included in the open-source software GATE. Results show that this method can lead to the same accuracy of conventional Monte Carlo methods while reducing the required computation time of up to two orders of magnitude, with the respect to the considered geometry. A database of dose curves for the case of monochromatic breast CT has been produced: it allows for a quick estimation of the delivered dose. A way to choose the best energy and the optimal photon flux was also proposed, which leads to a significant reduction of the delivered dose without any loss in terms of image quality. Most of the experimental and data reconstruction methods developed within this Thesis work can be applied also to other phase-contrast techniques. This Thesis shows that high resolution three dimensional diagnostic imaging of large and complex biological organs can, in principle, be performed at clinical compatible doses; this is the most significant contribution of the Thesis towards the clinical implementation of phase-contrast CT.Auf Phasenkontrast basierende Röntgentechniken sind innovative bildgebende Methoden, welche die Limitierungen der klassischen Radiologie überschreiten. Auβer der differentiellen Röntgenabsorption, auf der die herkömmliche Radiologie beruht, ist der Kontrast bei Phasenkontrast-Bildgebung durch die Brechungseffekte der Röntgenstrahlen innerhalb eines Gewebes gegeben. Die Kombination zwischen Phasenkontrast und quantitativer Computertomographie (CT) erlaubt eine höchstgenaue Rekonstruktion der Brechzahl der Gewebe. Aufgrund der hohen Empfindlichkeit dieser Methode, können tomographische Bilder mit einer klinisch verträglichen Dosis erzeugt werden. Aus all diesen Gründen, stellt Phasenkontrast-Bildgebung einen vielversprechenden Ansatz dar, welcher die diagnostische Röntgenbildgebung revolutionieren könnte. Verschiedene röntgenbildgebende Techniken werden als Phasenkontrast-Verfahren bezeichnet. Die vorliegende Doktorarbeit befasst sich mit der sogenannten Bildgebungsmethode mithilfe eines Analysatorkristalls (auf englisch: analyser-based imaging (ABI) ). ABI benutzt ein perfektes, zwischen der Probe und dem Detektor angeordnetes Kristall, um in der Probe stattfindenden Phaseneffekte zu veranschaulichen. Die quantitative Rekonstruktion des Brechungsindizes aus den CT-Daten ist jedoch nicht trivial und war vor dieser Arbeit nur für kleine Gegenstände beschrieben. Im Mittelpunkt dieser Dissertation stehen folgende wissenschaftliche Fragestellungen: (1) die Entwicklung theoretischer und rechnerischer Strategien, um die quantitative räumliche Verteilung des Brechungsindizes in größeren Organen aus biologischen Geweben (10 cm) unter Verwendung der ABI-Technik zu bilden und (2) die Vorbereitung von genauen und leistungsfähigen Rechenmitteln zur Abschätzung und Simulation der in größeren Proben bei einem CT-Bildgebungsversuch abgelagerten Strahlendosis zu treffen. Für die Bestimmung des Brechungsindizes wurden zwei geometrische Anordnungen in Betracht gezogen und untersucht, und zwar die Konfiguration auβerhalb (out-of-plane) bzw. in der Ebene (in-plane) der Probe. Erstere wird am häufigsten in der Fachliteratur zitiert und sieht vor, dass die Probe-Drehachse sich in der parallelen Ebene zur Achse des Analysatorkristalls befindet, wobei in der zweiteren Geometrie die Drehachse orthogonal zu jener Ebene ist. Die theoretische Studie, der technische Entwurf und die experimentelle Umsetzung der geometrischen Anordnung in der Probe-Ebene stellen die Hauptaufgaben dieser Arbeit dar. Ein erstes Experiment wurde durchgeführt, um die durch quantitative Phasenkontrast-CT nach in-plane-Modus erlangten Ergebnisse mit entsprechenden, auf Absorption basierenden CT-Versuchen zu vergleichen. Eine höhere Genauigkeit sowie eine bessere Übereinstimmung mit den theoretischen Dichtewerten wurden dadurch erzielt, dass man sich die Brechungseffekte zunutze macht, indem man die an die Probe gelieferte Dosis niedrig hält. Eine zweite Versuchsreihe wurde auβerdem auf menschliche Brüste ausgeführt, um die Effizienz sowohl der in-plane- als auch der out-of-plane-CT-Geometrien sowie die Leistungsfähigeit der entsprechenden Bildrekonstruktionsverfahren zu überprüfen. Die gleichen Experimentalbedingungen wurden auch anhand von numerischen Simulationen untersucht und die Ergebnisse miteinander verglichen. Diese Analyse zeigt, dass die in-plane-Geometrie die Erstellung genauerer dreidimensionaler Verteilungen der Brechzahl ermöglicht, während der out-of-plane-Fall eher für die Zwecke qualitativer Untersuchungen vorzuziehen ist. Fortschrittliche Prozeduren zur Verbesserung der Qualität von aufgezeichneten CT-Bildern wurden im Rahmen dieser Doktorarbeit konzipiert und entwickelt. Das Fazit: eine zweistufige Vorgehensweise wurde ermittelt und geprüft. Zunächst wird der Rauschpegel der Meβdaten über die Anwendung eines Zerlegungsalgorithmus mittels Wavelets gesenkt, anschlieβend gefolgt von einem Entfaltung-Verfahren. Die damit gewonnenen Bilder weisen eine erhöhte Schärfe der Schnittstellen auf. Die Objektkanten und das Signal-zu-Rausch-Verhältnis bleiben damit erhalten. Die zweite Fragestellung dieser Arbeit war es, Lösungansätze zu erarbeiten, um die während CT-Bildgebung-Messungen über complexe biologische Proben abgegebene Dosis möglichst rapide zu berechnen. Zu diesem Zweck wurde ein Verfahren zur Beschleunigung der Konvergenz von Monte-Carlo-Simulationen auf der Grundlage der Track-Length-Estimator-Methode entwickelt und in die Open-Source-Software GATE eingegliedert. Die bisherigen Ergebnisse zeigen, dass dieses Verfahren zur selben Genauigkeit der herkömmlichen Monte-Carlo-Methoden bei gleichzeitiger Minderung bis zu zwei Gröβenordnungen der zur Berechnung einer und der selben Geometrie notwendigen Rechenzeit führt. Eine Datenbank von Dosiskurven für den Fall von monochromatischer Brust-CT ist erzeugt worden, die eine schnelle Schätzung der abgegebenen Dosis erlaubt. Darüber hinaus wurde ein Lösungsweg zur Auswahl der besten Energie und des optimalen Photonenflusses vorgeschlagen, welcher eine bedeutende Abnahme der abgelieferten Dosis zur Folge hat, und zwar ohne Bildqualitätsverluste. Die meisten, im Rahmen dieser Doktorarbeit entwickelten Experimental- und Datenrekonstruktion-Verfahren können freilich auch an andere Phasenkontrast-Techniken angewendet werden. Es wird hiermit gezeigt, dass hochauflösende dreidimensionale bildgebende Verfahren zur Diagnostik gröβerer und komplexer biologischer Gegenstände bei klinisch verträglichen Dosen grundsätzlich eingesetzt werden können. Dies ist der nennenwerteste Beitrag dieser Dissertation zur klinischen Umsetzung der Phasenkontrast-CT

Contributions to the improvement of image quality in CBCT and CBμCT and application in the development of a CBμCT system

During the last years cone-beam x-ray CT (CBCT) has been established as a widespread imaging technique and a feasible alternative to conventional CT for dedicated imaging tasks for which the limited flexibility offered by conventional CT advises the development of dedicated designs. CBCT systems are starting to be routinely used in image guided radiotherapy; image guided surgery using C-arms; scan of body parts such as the sinuses, the breast or extremities; and, especially, in preclinical small-animal imaging, often coupled to molecular imaging systems. Despite the research efforts advocated to the advance of CBCT, the challenges introduced by the use of large cone angles and two-dimensional detectors are a field of vigorous research towards the improvement of CBCT image quality. Moreover, systems for small-animal imaging add to the challenges posed by clinical CBCT the need of higher resolution to obtain equivalent image quality in much smaller subjects. This thesis contributes to the progress of CBCT imaging by addressing a variety of issues affecting image quality in CBCT in general and in CBCT for small-animal imaging (CBμCT). As part of this work we have assessed and optimized the performance of CBμCT systems for different imaging tasks. To this end, we have developed a new CBμCT system with variable geometry and all the required software tools for acquisition, calibration and reconstruction. The system served as a tool for the optimization of the imaging process and for the study of image degradation effects in CBμCT, as well as a platform for biological research using small animals. The set of tools for the accurate study of CBCT was completed by developing a fast Monte Carlo simulation engine based on GPUs, specifically devoted to the realistic estimation of scatter and its effects on image quality in arbitrary CBCT configurations, with arbitrary spectra, detector response, and antiscatter grids. This new Monte Carlo engine outperformed current simulation platforms by more than an order of magnitude. Due to the limited options for simulation of spectra in microfocus x-ray sources used in CBμCT, we contributed in this thesis a new spectra generation model based on an empirical model for conventional radiology and mammography sources modified in accordance to experimental data. The new spectral model showed good agreement with experimental exposure and attenuation data for different materials. The developed tools for CBμCT research were used for the study of detector performance in terms of dynamic range. The dynamic range of the detector was characterized together with its effect on image quality. As a result, a new simple method for the extension of the dynamic range of flat-panel detectors was proposed and evaluated. The method is based on a modified acquisition process and a mathematical treatment of the acquired data. Scatter is usually identified as one of the major causes of image quality degradation in CBCT. For this reason the developed Monte Carlo engine was applied to the in-depth study of the effects of scatter for a representative range of CBCT embodiments used in the clinical and preclinical practice. We estimated the amount and spatial distribution of the total scatter fluence and the individual components within. The effect of antiscatter grids in improving image quality and in noise was also evaluated. We found a close relation between scatter and the air gap of the system, in line with previous results in the literature. We also observed a non-negligible contribution of forward-directed scatter that is responsible to a great extent for streak artifacts in CBCT. The spatial distribution of scatter was significantly affected by forward scatter, somewhat challenging the usual assumption that the scatter distribution mostly contains low-frequencies. Antiscatter grids showed to be effective for the reduction of cupping, but they showed a much lower performance when dealing with streaks and a shift toward high frequencies of the scatter distributions. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------A lo largo de los últimos años, el TAC de rayos X de haz cónico (CBCT, de “conebeam” CT) se ha posicionado como una de las técnicas de imagen más ampliamente usadas. El CBCT se ha convertido en una alternativa factible al TAC convencional en tareas de imagen específicas para las que la flexibilidad limitada ofrecida por este hace recomendable el desarrollo de sistemas de imagen dedicados. De esta forma, el CBCT está empezando a usarse de forma rutinaria en varios campos entre los que se incluyen la radioterapia guiada por imagen, la cirugía guiada por imagen usando arcos en C, imagen de partes de la anatomía en las que el TAC convencional no es apropiado, como los senos nasales, las extremidades o la mama, y, especialmente el campo de imagen preclínica con pequeño animal. Los sistemas CBCT usados en este último campo se encuentran habitualmente combinados con sistemas de imagen molecular. A pesar del trabajo de investigación dedicado al avance de la técnica CBCT en los últimos años, los retos introducidos por el uso de haces cónicos y de detectores bidimensionales son un campo candente para la investigación médica, con el objetivo de obtener una calidad de imagen equivalente o superior a la proporcionada por el TAC convencional. En el caso de imagen preclínica, a los retos generados por el uso de CBCT se une la necesidad de una mayor resolución de imagen que permita observar estructuras anatómicas con el mismo nivel de detalle obtenido para humanos. Esta tesis contribuye al progreso del CBCT mediante el estudio de usa serie de efectos que afectan a la calidad de imagen de CBCT en general y en el ámbito preclínico en particular. Como parte de este trabajo, hemos evaluado y optimizado el rendimiento de sistemas CBCT preclínicos en función de la tarea de imagen concreta. Con este fin se ha desarrollado un sistema CBCT para pequeños animales con geometría variable y todas las herramientas necesarias para la adquisición, calibración y reconstrucción de imagen. El sistema sirve como base para la optimización de protocolos de adquisición y para el estudio de fuentes de degradación de imagen además de constituir una plataforma para la investigación biológica en pequeño animal. El conjunto de herramientas para el estudio del CBCT se completó con el desarrollo de una plataforma acelerada de simulación Monte Carlo basada en GPUs, optimizada para la estimación de radiación dispersa en CBCT y sus efectos en la calidad de imagen. La plataforma desarrollada supera el rendimiento de las actuales en más de un orden de magnitud y permite la inclusión de espectros policromáticos de rayos X, de la respuesta realista del detector y de rejillas antiscatter. Debido a las escasas opciones ofrecidas por la literatura para la estimación de espectros de rayos X para fuentes microfoco usadas en imagen preclínica, en esta tesis se incluye el desarrollo de un nuevo modelo de generación de espectros, basado en un modelo existente para fuentes usadas en radiología y mamografía. El modelo fue modificado a partir de datos experimentales. La precisión del modelo presentado se comprobó mediante datos experimentales de exposición y atenuación para varios materiales. Las herramientas desarrolladas se usaron para estudiar el rendimiento de detectores de rayos tipo flat-panel en términos de rango dinámico, explorando los límites impuestos por el mismo en la calidad de imagen. Como resultado se propuso y evaluó un método para la extensión del rango dinámico de este tipo de detectores. El método se basa en la modificación del proceso de adquisición de imagen y en una etapa de postproceso de los datos adquiridos. El simulador Monte Carlo se empleó para el estudio detallado de la naturaleza, distribución espacial y efectos de la radiación dispersa en un rango de sistemas CBCT que cubre el espectro de aplicaciones propuestas en el entorno clínico y preclínico. Durante el estudio se inspeccionó la cantidad y distribución espacial de radiación dispersa y de sus componentes individuales y el efecto causado por la inclusión de rejillas antiscatter en términos de mejora de calidad de imagen y de ruido en la imagen. La distribución de radiación dispersa mostró una acentuada relación con la distancia entre muestra y detector en el equipo, en línea con resultados publicados previamente por otros autores. También se encontró una influencia no despreciable de componentes de radiación dispersa con bajos ángulos de desviación, poniendo en tela de juicio la tradicional asunción que considera que la distribución espacial de la radiación dispersa está formada casi exclusivamente por componentes de muy baja frecuencia. Las rejillas antiscatter demostraron ser efectivas para la reducción del artefacto de cupping, pero su efectividad para tratar artefactos en forma de línea (principalmente formados por radiación dispersa con bajo ángulo de desviación) resultó mucho menor. La inclusión de estas rejillas también enfatiza las componentes de alta frecuencia de la distribución espacial de la radiación dispersa

Optimization strategies for respiratory motion management in stereotactic body radiation therapy

Various challenges arise during the treatment of lung tumors with stereotactic body radiation therapy (SBRT), which is a form of hypofractionated high precision conformal radiation therapy delivered to small targets. The dose is applied in only a few fractions and respiratory organ and tumor motion is a source of uncertainty additional to interfractional set-up errors. Respiratory organ and tumor motion is highly patient-specific and it affects the whole radiotherapy treatment chain. In this thesis, motion management techniques for SBRT are evaluated and improved in a clinical setting. A clinical need for improvement has been present at the LMU university hospital for each issue addressed in this thesis: Initially, the usage of respiratory correlated computed tomography (4DCT), which is vital for SBRT treatment, was seen as impractical and prone to uncertainties in the data reconstruction in its current form. Therefore, the 4DCT reconstruction workflow has been improved to minimize these potential error sources. Secondly, treatment planning for tumors affected by respiratory motion was evaluated and subsequently improved. Finally, the treatment technique of respiratory gating was implemented at the clinic, which led to the need of evaluating the respiratory gating characteristics of the novel system configuration. At first, the 4DCT reconstruction workflow used in clinical practice was investigated, as in the presence of respiratory motion the knowledge of tumor position over time is essential in SBRT treatments. Using 4DCT, the full motion range of the individual tumor can be determined. However, certain 4DCT reconstruction methods can under- or overestimate tumor motion due to limitations in the data acquisition scheme and due to the incorrect sorting of certain X-ray computed tomography (CT) image slices into different respiratory phases. As the regular clinical workflow of cycle-based sorting (CBS) without maximum inspiration detection (and therefore no clear starting point for the individual breathing cycles) seemed to be affected by these potential errors, the usage of CBS with correct maximum detection and another sorting algorithm of the respiration states, so-called local amplitude-based sorting (LAS), both have been implemented for a reduction of image artifacts and improved 4DCT quality. The three phase binning algorithms have been investigated in a phantom study (using 10 different breathing waveforms) and in a patient study (with 10 different patients). The mis-representation of the tumor volume was reduced in both implemented sorting algorithms compared to the previously used CBS approach (without correct maximum detection) in the phantom and the patient study. The clinical recommendation was the use of CBS with improved maximum detection, as too many manual interventions would be needed for the LAS workflow. Secondly, a combination of the actual patient breathing trace during treatment, the log files generated by the linear accelerator (LINAC), and Monte Carlo (MC) four-dimensional (4D) dose calculations for each individual fraction was implemented as a 4D dose evaluation tool. This workflow was tested in a clinical environment for SBRT treatment planning on multiple CT datasets featuring: a native free-breathing 3DCT, an average intensity projection (AIP) as well as a maximum intensity projection (MIP), both obtained from the patient's 4DCT, and density overrides (DOs) in a 3DCT. This study has been carried out for 5 SBRT patients for three-dimensional conformal radiation therapy (3D-CRT) and volumetric modulated arc therapy (VMAT) treatment plans. The dose has been recalculated on each 4DCT breathing phase according the the patient's breathing waveform and accumulated to the gross tumor volume (GTV) at the end-of-exhale (EOE) breathing phase using deformable image registration. Even though the least differences in planned and recalculated dose were found for AIP and MIP treatment planning, the results indicate a strong dependency on individual tumor motion due to the variability of breathing motion in general, and on tumor size. The combination of the patient's individual breathing trace during each SBRT fraction with 4D MC dose calculation based on the LINAC log file information leads to a good approximation of actual dose delivery. Finally, in order to ensure precise and accurate treatment for respiratory gating techniques, the technical characteristics of the LINAC in combination with a breathing motion monitoring system as s surrogate for tumor motion have to be identified. The dose delivery accuracy and the latency of a surface imaging system in connection with a modern medical LINAC were investigated using a dynamic breathing motion phantom. The dosimetric evaluation has been carried out using a static 2D-diode array. The measurement of the dose difference between gated and ungated radiation delivery was found to be below 1% (for clinical relevant gating levels of about 30%). The beam-on latency, or time delay, determined using radiographic films was found to be up to 851 ms±100 ms. With these known parameters, an adjustment of the pre-selected gating level or the internal target volume (ITV) margins could be made. With the highly patient-specific character of respiratory motion, lung SBRT faces many additional challenges besides the specific issues addressed in this thesis. However, the findings of this thesis have improved clinical workflows at the Department of Radiation Oncology of the LMU University hospital. In a future perspective, a workflow using evaluation of the actual 4D dose in combination with accurate 4DCT image acquisition and specialized treatment delivery (such as respiratory gating) has the potential for a safe further reduction of treatment margins and increased sparing of organs-at-risk (OARs) in SBRT without compromising tumor dose targeting accuracy

Development and validation of two novel x-ray filters in computed tomography with focus on fluence modulation for region-of-interest imaging

Die Röntgen-Computertomographie (CT) hat sich zu einem zentralen Element der klinischen Bildgebung entwickelt. Sie liefert Schichtbilder, die sich durch eine hohe zeitliche und räumliche Auflösung bei sehr kurzen Aufnahmezeiten auszeichnen. Allerdings verwendet die CT zur Bildaufnahme ionisierende Röntgenstrahlung, die ein potenzielles Gesundheitsrisiko für den Patienten darstellt. Über die Jahre wurden viele Maßnahmen ergriffen, um die Strahlendosis zu reduzieren. Ein Ansatz ist die dynamische Vorfilterung des Röntgenstrahls, um die Abschwächung der Röntgenstrahlung durch den Patienten, die über die Projektionen und die Fächerstrahlbreite variiert, zu kompensieren. Bowtie-Filter moderner CT Systeme nach dem Stand der Technik sind jedoch statische Vollkörper und können sich nicht an die individuelle Patientenschwächung anpassen. Eine Lösung für patienten- und aufgabenspezifische CT Bildgebung ist die Modulation des Fluenzbereichs (FFM) unter Verwendung eines dynamischen Strahlabschwächers (DBA). DBAs ermöglichen es, die Röntgenfluenz während der Datenaufnahme anzupassen. Existierende DBA-Konzepte zeigen jedoch grundsätzliche Schwachstellen (z.B. zu groß oder zu langsam), die eine Realisierung in klinischen CT Systemen ausschließen. In dieser Thesis wurden zwei grundlegend neue DBA-Konzepte entwickelt, um die mangelnde Flexibilität derzeitiger Bowtie-Filter und die Einschränkungen bisheriger DBA-Ansätze zu überwinden. Der lamellenbasierte DBA (sbDBA) besteht aus einer Anordnung von stark röntgenabsorbierenden Lamellen. Je nach Verkippung des sbDBA verändert sich die Transmission durch den sbDBA – vergleichbar mit Jalousien. Auch der artverwandte, z-ausgerichtete sbDBA (z-sbDBA) besitzt Absorptionslamellen zur FFM, verwendet jedoch eine überarbeitete Strukturierung und eine einfachere Mechanik. Ausgehend von einfachen Skizzen wurden reale Prototypen des sbDBA und des z-sbDBA gebaut und in ein klinisches CT System integriert. Im ersten Teil dieser Arbeit wurden das modifizierte CT System und Monte-Carlo Simulationen, die dieses CT System nachbilden, verwendet, um die DBAs zu untersuchen. In Versuchsmessungen konnten beide DBAs verschiedene Transmissionprofile erzeugen und somit FFM – die Hauptfunktion eines DBA – realisieren. Während der sbDBA auch die Verschiebung der Maximaltransmission erlaubte, wurden mit dem z-sbDBA geeignetere Verläufe der Transmissionsprofile erzielt. Ein Vergleich spektraler Abhängigkeit der Transmission und DBA-induzierter Streustrahlung zeigte bemerkenswerte Vorteile gegenüber herkömmlichen Bowtie-Filtern. Obwohl einzelne Ringartefakte in ersten Bildrekonstruktionen Herausforderung hinsichtlich der mechanischen Stabilität der DBAs aufzeigten, war die Bildqualität insgesamt vielversprechend. Im zweiten Teil wurde das Potenzial für Zielvolumen (ROI) Bildgebung untersucht, bei der nur ein bestimmter Bereich mit hoher Qualität dargestellt und im umliegenden Gewebe die Dosis minimiert wird. Zunächst wurde hierzu ein Optimierungskriterium entwickelt, mit dem die Kippbewegungen der DBAs hinsichtlich eines diagnostischen Ziels optimiert werden. Dabei soll die Patientendosis minimiert und die Bildqualität innerhalb der ROI maximiert werden. Die erzeugten DBA-Trajektorien passten die emittierte Röntgenfluenz an die Geometrie der ROI an. Anschließend wurden verschiedene FFM-Konfigurationen, einschließlich Röhrenstrommodulation und zweier Bowtie-Filter, mit den DBAs bezüglich ihrer Dosiseffizienz bei ROI-Bildgebung verglichen. Es zeigte sich, dass die DBAs die Röntgenstrahlung effizienter einsetzten als Bowtie-Filter moderner CT Systeme: Bei Verwendung der DBAs konnten die ROIs bei gleichbleibender Bildqualität mit bis zu 30 % (z-sbDBA) bzw. 60 % (sbDBA) weniger Dosis im Vergleich zu einem typischen Bowtie-Filter dargestellt werden. In dieser Arbeit wurden zwei neuartige DBA-Konzepte entwickelt und in ein klinisches CT System installiert. Diese DBAs wurden hinsichtlich FFM erfolgreich validiert und zeigten bei ROI-Bildgebung erhebliches Dosiseinsparpotential im Vergleich zu heutiger FFM-Technik. Die vielversprechenden Ergebnisse bilden eine Grundlage für zukünftige Dosisreduktionen und ebnen den Weg für ROI-Bildgebung in der CT Diagnostik.X-ray computed tomography (CT) imaging has become a workhorse of today’s clinical imaging. It provides cross-sectional diagnostic images featuring high temporal and spatial resolution at very short acquisition times. However, CT images are acquired using x-rays, which bears a potential health detriment to the patient due to ionization radiation. Over the decades, many efforts have been undertaken to reduce the radiation burden. One approach is to employ dynamic pre-filtration of the x-ray beam to compensate for the patient’s x-ray attenuation that changes across the projections and the fan beam angle. State-of-the-art bowtie filters in clinical CT systems, however, are static and therefore cannot adapt to patient attenuation individually. A solution for patient- and task-specific CT imaging is fluence field modulation (FFM) by employing a dynamic beam attenuator (DBA). DBAs are capable of adapting the x-ray fluence during the data acquisition. Existing DBA concepts, however, suffer from inherent limitations (e.g., too large or too slow) that preclude an implementation in clinical CT systems. In this thesis, two fundamentally new DBA concepts were developed to overcome the lack of flexibility of present bowtie filters and the pitfalls of previous DBA approaches. The sheet-based DBA (sbDBA) was composed of an array of highly x-ray attenuating sheets. Depending on the way the sbDBA was tilted, the transmission through the sbDBA changed – comparable to Persian blinds. Likewise, the z-aligned sbDBA (z-sbDBA) employed attenuation sheets for FFM, although it used a revised structuring and simplified mechanics. Starting from simple sketches, physical prototypes of the sbDBA and the z-sbDBA were built and integrated into a clinical CT system. In the first part of this thesis, the DBAs were investigated using the modified CT system and Monte Carlo simulations mimicking this CT system. In experimental measurements, both DBAs were able to realize a wide range of transmission profiles and therefore successfully demonstrated their feasibility of FFM — the key function of a DBA. While the sbDBA allowed to shape the transmission profiles more flexibly by shifting the peak transmission also laterally, the z-sbDBA realized more suitable shapes. A comparison regarding the spectral dependency of the transmission and attenuator-induced scatter revealed remarkable advantages over conventional bowtie filters. Although ring artifacts in first-time image reconstructions unveiled challenges concerning the mechanical reliability of the DBAs, the overall image quality was promising. In the second part, the potential for region-of-interest (ROI) imaging, where only a specific region is imaged at high quality while the dose is minimized in surrounding tissue, was explored. In the first step, an optimization objective was developed to optimize the angular movements of the DBA regarding a given imaging task. The optimization aims at minimizing the patient dose and maximizing the image quality inside the ROI. The optimized DBA movements reasonably adapted the emitted x-ray fluence to the geometry of the ROI. In the second step, different FFM configurations, including tube current modulation and different bowtie filters, were compared with the DBAs regarding their dose efficiency in ROI imaging. The DBAs were shown to exploit the x-ray radiation more efficiently than the bowtie filters of modern CT systems: using the DBAs, the ROIs were imaged with up to 30 % (z-sbDBA) or 60 % (sbDBA) less radiation dose compared to a typical bowtie filter while maintaining the image quality in the ROI. In conclusion, two novel DBA concepts were developed and installed into a clinical CT system. These DBAs were successfully validated regarding FFM and demonstrated a remarkable dose saving potential in ROI imaging compared to state-of-the-art FFM technology. The promising results give rise for future radiation dose reductions and pave the way to ROI imaging in diagnostic CT

Optimization strategies for respiratory motion management in stereotactic body radiation therapy

Various challenges arise during the treatment of lung tumors with stereotactic body radiation therapy (SBRT), which is a form of hypofractionated high precision conformal radiation therapy delivered to small targets. The dose is applied in only a few fractions and respiratory organ and tumor motion is a source of uncertainty additional to interfractional set-up errors. Respiratory organ and tumor motion is highly patient-specific and it affects the whole radiotherapy treatment chain. In this thesis, motion management techniques for SBRT are evaluated and improved in a clinical setting. A clinical need for improvement has been present at the LMU university hospital for each issue addressed in this thesis: Initially, the usage of respiratory correlated computed tomography (4DCT), which is vital for SBRT treatment, was seen as impractical and prone to uncertainties in the data reconstruction in its current form. Therefore, the 4DCT reconstruction workflow has been improved to minimize these potential error sources. Secondly, treatment planning for tumors affected by respiratory motion was evaluated and subsequently improved. Finally, the treatment technique of respiratory gating was implemented at the clinic, which led to the need of evaluating the respiratory gating characteristics of the novel system configuration. At first, the 4DCT reconstruction workflow used in clinical practice was investigated, as in the presence of respiratory motion the knowledge of tumor position over time is essential in SBRT treatments. Using 4DCT, the full motion range of the individual tumor can be determined. However, certain 4DCT reconstruction methods can under- or overestimate tumor motion due to limitations in the data acquisition scheme and due to the incorrect sorting of certain X-ray computed tomography (CT) image slices into different respiratory phases. As the regular clinical workflow of cycle-based sorting (CBS) without maximum inspiration detection (and therefore no clear starting point for the individual breathing cycles) seemed to be affected by these potential errors, the usage of CBS with correct maximum detection and another sorting algorithm of the respiration states, so-called local amplitude-based sorting (LAS), both have been implemented for a reduction of image artifacts and improved 4DCT quality. The three phase binning algorithms have been investigated in a phantom study (using 10 different breathing waveforms) and in a patient study (with 10 different patients). The mis-representation of the tumor volume was reduced in both implemented sorting algorithms compared to the previously used CBS approach (without correct maximum detection) in the phantom and the patient study. The clinical recommendation was the use of CBS with improved maximum detection, as too many manual interventions would be needed for the LAS workflow. Secondly, a combination of the actual patient breathing trace during treatment, the log files generated by the linear accelerator (LINAC), and Monte Carlo (MC) four-dimensional (4D) dose calculations for each individual fraction was implemented as a 4D dose evaluation tool. This workflow was tested in a clinical environment for SBRT treatment planning on multiple CT datasets featuring: a native free-breathing 3DCT, an average intensity projection (AIP) as well as a maximum intensity projection (MIP), both obtained from the patient's 4DCT, and density overrides (DOs) in a 3DCT. This study has been carried out for 5 SBRT patients for three-dimensional conformal radiation therapy (3D-CRT) and volumetric modulated arc therapy (VMAT) treatment plans. The dose has been recalculated on each 4DCT breathing phase according the the patient's breathing waveform and accumulated to the gross tumor volume (GTV) at the end-of-exhale (EOE) breathing phase using deformable image registration. Even though the least differences in planned and recalculated dose were found for AIP and MIP treatment planning, the results indicate a strong dependency on individual tumor motion due to the variability of breathing motion in general, and on tumor size. The combination of the patient's individual breathing trace during each SBRT fraction with 4D MC dose calculation based on the LINAC log file information leads to a good approximation of actual dose delivery. Finally, in order to ensure precise and accurate treatment for respiratory gating techniques, the technical characteristics of the LINAC in combination with a breathing motion monitoring system as s surrogate for tumor motion have to be identified. The dose delivery accuracy and the latency of a surface imaging system in connection with a modern medical LINAC were investigated using a dynamic breathing motion phantom. The dosimetric evaluation has been carried out using a static 2D-diode array. The measurement of the dose difference between gated and ungated radiation delivery was found to be below 1% (for clinical relevant gating levels of about 30%). The beam-on latency, or time delay, determined using radiographic films was found to be up to 851 ms±100 ms. With these known parameters, an adjustment of the pre-selected gating level or the internal target volume (ITV) margins could be made. With the highly patient-specific character of respiratory motion, lung SBRT faces many additional challenges besides the specific issues addressed in this thesis. However, the findings of this thesis have improved clinical workflows at the Department of Radiation Oncology of the LMU University hospital. In a future perspective, a workflow using evaluation of the actual 4D dose in combination with accurate 4DCT image acquisition and specialized treatment delivery (such as respiratory gating) has the potential for a safe further reduction of treatment margins and increased sparing of organs-at-risk (OARs) in SBRT without compromising tumor dose targeting accuracy