HIGH-THROUGHPUT MAPPING OF THE BIOLOGICAL EFFECTS OF PARTICLE THERAPY

Radiation therapy is an essential tool in the cure of many cancer patients. Charged particle based radiation therapies are gaining momentum as the physical dose distributions of ions are superior to standard photons due their limited range. Additionally, charged particle radiation has been shown to have linear energy transfer (LET) specific relative biological effectiveness (RBE) when compared to photons. It is essential to employ accurate biophysical models for particle beams in order to maximize the therapeutic potential of particle therapy through the introduction of biologically optimized treatment planning. The development of such models requires the support of large amounts of accurate physical and biological data for each pristine beam. Unfortunately, such data are limited and difficult to obtain. This work presents the development of a high-throughput irradiation methodology that utilizes automated high-throughput screening techniques to sample multiple locations along a therapeutic ion therapy beam in a single irradiation. Using a special irradiation apparatus designed and validated by our group, RBEs of adherent lung cancer cell lines at 12 positions along proton beams at the MD Anderson Proton Therapy Center (PTC) and the Heidelberg Ion Therapy (HIT) facility were measured. RBEs for helium and carbon ion beams were also measured at the HIT facility. This system was further employed to perform image-based, high-throughput mechanistic DNA damage response studies following exposure to particles at varying LETs. Furthermore, the biological response to particles was examined in additional model systems including glioma stem cell spheroids and normal rat brain organoids. For protons, all model systems demonstrated a rapid rise in RBE beyond the Bragg peak. These findings contrast with several current model predictions which assume the RBE trend linearly scales with proton LET. For the heavier particle measurements, we found absolute RBE values and relative trends comparable to literature values. However, overkill effects occurred for lower LETs than previously reported. DNA damage response assays correlated with RBE measurements. The discrepancy between model predictions and experimental data, especially in the high-LET regions, requires rigorous experimental validation to ensure the accuracy of existing models. The developed high-throughput irradiation system enables the rapid measurement of biological response data which will contribute to a more complete mapping of particle biological effects as well as biological susceptibilities of different cell types to charged particle radiation. Ultimately, this knowledge will contribute to more comprehensive biophysical models and the production of biologically optimized intensity-modulated particle therapy plans

APPLYING OPERATIONS RESEARCH MODELS TO PROBLEMS IN HEALTH CARE

Intensity- modulated radiation therapy is a form of cancer treatment that directs high energy x-rays to irradiate a tumor volume. In order to minimize the damage to surround-ing tissue the radiation is delivered from multiple angles. The selection of angles is an NP-hard problem and is currently done manually in most hospitals. We use previously evaluated treatment plans to train a machine learning model to sort potential treatment plans. By sorting potential treatment plans we can find better solutions while only evalu-ating a fifth as many plans. We then construct a genetic algorithm and use our machine learning models to search the space of all potential treatment plans to suggest a potential best plan. Using the genetic algorithm we are able to find plans 2% better on average than the previously best known plans. Proton therapy is a new form of radiation therapy. We simulated a proton therapy treatment center in order to optimize patient throughput and minimize patient wait time. We are able to schedule patients reducing wait times between 20% and 35% depending on patient tardiness and absenteeism. Finally, we analyzed the impact of operations research on the treatment of pros-tate cancer. We reviewed the work that has been published in both operations research and medical journals, seeing how it has impacted policy and doctor recommendations

A new detector for the beam energy measurement in proton therapy: a feasibility study

Fast procedures for the beam quality assessment and for the monitoring of beam energy modulations during the irradiation are among the most urgent improvements in particle therapy. Indeed, the online measurement of the particle beam energy could allow assessing the range of penetration during treatments, encouraging the development of new dose delivery techniques for moving targets. Towards this end, the proof of concept of a new device, able to measure in a few seconds the energy of clinical proton beams (from 60 to 230 MeV) from the Time of Flight (ToF) of protons, is presented. The prototype consists of two Ultra Fast Silicon Detector (UFSD) pads, featuring an active thickness of 80 um and a sensitive area of 3 x 3 mm2, aligned along the beam direction in a telescope configuration, connected to a broadband amplifier and readout by a digitizer. Measurements were performed at the Centro Nazionale di Adroterapia Oncologica (CNAO, Pavia, Italy), at five different clinical beam energies and four distances between the sensors (from 7 to 97 cm) for each energy. In order to derive the beam energy from the measured average ToF, several systematic effects were considered, Monte Carlo simulations were developed to validate the method and a global fit approach was adopted to calibrate the system. The results were benchmarked against the energy values obtained from the water equivalent depths provided by CNAO. Deviations of few hundreds of keV have been achieved for all considered proton beam energies for both 67 and 97 cm distances between the sensors and few seconds of irradiation were necessary to collect the required statistics. These preliminary results indicate that a telescope of UFSDs could achieve in a few seconds the accuracy required for the clinical application and therefore encourage further investigations towards the improvement and the optimization of the present prototype

Development of Dose Verification Detectors Towards Improving Proton Therapy Outcomes

abstract: The challenge of radiation therapy is to maximize the dose to the tumor while simultaneously minimizing the dose elsewhere. Proton therapy is well suited to this challenge due to the way protons slow down in matter. As the proton slows down, the rate of energy loss per unit path length continuously increases leading to a sharp dose near the end of range. Unlike conventional radiation therapy, protons stop inside the patient, sparing tissue beyond the tumor. Proton therapy should be superior to existing modalities, however, because protons stop inside the patient, there is uncertainty in the range. “Range uncertainty” causes doctors to take a conservative approach in treatment planning, counteracting the advantages offered by proton therapy. Range uncertainty prevents proton therapy from reaching its full potential. A new method of delivering protons, pencil-beam scanning (PBS), has become the new standard for treatment over the past few years. PBS utilizes magnets to raster scan a thin proton beam across the tumor at discrete locations and using many discrete pulses of typically 10 ms duration each. The depth is controlled by changing the beam energy. The discretization in time of the proton delivery allows for new methods of dose verification, however few devices have been developed which can meet the bandwidth demands of PBS. In this work, two devices have been developed to perform dose verification and monitoring with an emphasis placed on fast response times. Measurements were performed at the Mayo Clinic. One detector addresses range uncertainty by measuring prompt gamma-rays emitted during treatment. The range detector presented in this work is able to measure the proton range in-vivo to within 1.1 mm at depths up to 11 cm in less than 500 ms and up to 7.5 cm in less than 200 ms. A beam fluence detector presented in this work is able to measure the position and shape of each beam spot. It is hoped that this work may lead to a further maturation of detection techniques in proton therapy, helping the treatment to reach its full potential to improve the outcomes in patients.Dissertation/ThesisDoctoral Dissertation Physics 201

FRoG: a fast robust analytical dose engine on GPU for p, 4He, 12C and 16O particle therapy

Radiotherapy with protons and heavier ions landmarks a novel era in the field of highprecision cancer therapy. To identify patients most benefiting from this technologically demanding therapy, fast assessment of comparative treatment plans utilizing different ion species is urgently needed. Moreover, to overcome uncertainties of actual in-vivo physical dose distribution and biological effects elicited by different radiation qualities, development of a reliable high-throughput algorithm is required. To this end, we engineered a unique graphics processing unit (GPU) based software architecture allowing rapid and robust dose calculation. Fast dose Recalculation on GPU (FRoG) currently operates with four particle beams, i.e., raster-scanning proton, helium, carbon and oxygen ions. Designed to perform fast and accurate calculations for both physical and biophysical quantities, FRoG operates an advanced analytical pencil beam algorithm using parallelized procedures on a GPU. Clinicians and medical physicists can assess both dose and dose-averaged linear energy transfer (LET) distributions for proton therapy (and in turn effective dose by applying variable RBE schemes) to further scrutinize plans for acceptance or potential re-planning purposes within minutes. In addition, various biological model predictions are readily accessible for heavy ion therapy, such as the local effect model (LEM) and microdosimetric kinetic model (MKM). FRoG has been extensively benchmarked against gold standard Monte Carlo simulations and experimental data. Evaluating against commercial treatment planning systems demonstrates the strength of FRoG in better predicting dose distributions in complex clinical settings. In preparation for the upcoming translation of novel ions, case-/disease-specific ion-beam selection and advanced multi-particle treatment modalities at the Heidelberg Ion-beam Therapy Center (HIT), we quantified the accuracy limits in particle therapy treatment planning under complex heterogeneous conditions for the four ions (p, 4He, 12C, 16O) for various dose engines, both analytical algorithms and Monte Carlo code. Devised in-house, FRoG landmarks the first GPU-based treatment planning system (non commercial) for raster-scanning 4He ion beams, with an official treatment program set for early 2020. Since its inception, FRoG has been installed and is currently in operation clinically at four centers across Europe: HIT (Heidelberg, Germany), CNAO (Pavia, Italy) , Aarhus (Denmark) and the Normandy Proton Therapy Center (Caen, France). Here, the development and validation of FRoG as well as clinical investigations and advanced topics in particle therapy dose calculation are covered. The thesis is presented in cumulative format and comprises four peer reviewed publications

Nuclear methods for real-time range verification in proton therapy based on prompt gamma-ray imaging

Accelerated protons are excellent candidates for treating several types of tumours. Such charged particles stop at a defined depth, where their ionisation density is maximum. As the dose deposit beyond this distal edge is very low, proton therapy minimises the damage to normal tissue compared to photon therapy. Nonetheless, inherent range uncertainties cast doubts on the irradiation of tumours close to organs at risk and lead to the application of conservative safety margins. This constrains significantly the potential benefits of proton over photon therapy and limits its ultimate aspirations. Prompt gamma rays, a by-product of the irradiation that is correlated to the dose deposition, are reliable signatures for the detection of range deviations and even for three-dimensional in vivo dosimetry. In this work, two methods for Prompt Gamma-ray Imaging (PGI) are investigated: the Compton camera (Cc) and the Prompt Gamma-ray Timing (PGT). Their applicability in a clinical scenario is discussed and compared. The first method aspires to reconstruct the prompt gamma ray emission density map based on an iterative imaging algorithm and multiple position sensitive gamma ray detectors. These are arranged in scatterer and absorber plane. The second method has been recently proposed as an alternative to collimated PGI systems and relies on timing spectroscopy with a single monolithic detector. The detection times of prompt gamma rays encode essential information about the depth-dose profile as a consequence of the measurable transit time of ions through matter. At Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and OncoRay, detector components are characterised in realistic radiation environments as a step towards a clinical Cc. Conventional block detectors deployed in commercial Positron Emission Tomography (PET) scanners, made of Cerium-doped lutetium oxyorthosilicate - Lu2SiO5:Ce (LSO) or Bismuth Germanium Oxide - Bi4Ge3O12 (BGO) scintillators, are suitable candidates for the absorber of a Cc due to their high density and absorption efficiency with respect to the prompt gamma ray energy range (several MeV). LSO and BGO block detectors are compared experimentally in clinically relevant radiation fields in terms of energy, spatial and time resolution. On a different note, two BGO block detectors (from PET scanners), arranged as the BGO block Compton camera (BbCc), are deployed for simple imaging tests with high energy prompt gamma rays produced in homogeneous Plexiglas targets by a proton pencil beam. The rationale is to maximise the detection efficiency in the scatterer plane despite a moderate energy resolution. Target shifts, increase of the target thickness and beam energy variation experiments are conducted. Concerning the PGT concept, in a collaboration among OncoRay, HZDR and IBA, the first test at a clinical proton accelerator (Westdeutsches Protonentherapiezentrum Essen) with several detectors and heterogeneous phantoms is performed. The sensitivity of the method to range shifts is investigated, the robustness against background and stability of the beam bunch time profile is explored, and the bunch time spread is characterised for different proton energies. With respect to the material choice for the absorber of the Cc, the BGO scintillator closes the gap with respect to the brighter LSO. The reason behind is the high energies of prompt gamma rays compared to the PET scenario, which increase significantly the energy, spatial and time resolution of BGO. Regarding the BbCc, shifts of a point-like radioactive source are correctly detected, line sources are reconstructed, and one centimetre proton range deviations are identified based on the evident changes of the back projection images. Concerning the PGT experiments, for clinically relevant doses, range differences of five millimetres in defined heterogeneous targets are identified by numerical comparison of the spectrum shape. For higher statistics, range shifts down to two millimetres are detectable. Experimental data are well reproduced by analytical modelling. The Cc and the PGT are ambitious approaches for range verification in proton therapy based on PGI. Intensive detector characterisation and tests in clinical facilities are mandatory for developing robust prototypes, since the energy range of prompt gamma rays spans over the MeV region, not used traditionally in medical applications. Regarding the material choice for the Cc: notwithstanding the overall superiority of LSO, BGO catches up in the field of PGI. It can be considered as a competitive alternative to LSO for the absorber plane due to its lower price, higher photoabsorption efficiency, and the lack of intrinsic radioactivity. The results concerning the BbCc, obtained with relatively simple means, highlight the potential application of Compton cameras for high energy prompt gamma ray imaging. Nevertheless, technical constraints like the low statistics collected per pencil beam spot (if clinical currents are used) question their applicability as a real-time and in vivo range verification method in proton therapy. The PGT is an alternative approach, which may have faster translation into clinical practice due to its lower price and higher efficiency. A proton bunch monitor, higher detector throughput and quantitative range retrieval are the upcoming steps towards a clinically applicable prototype, that may detect significant range deviations for the strongest beam spots. The experimental results emphasise the prospects of this straightforward verification method at a clinical pencil beam and settle this novel approach as a promising alternative in the field of in vivo dosimetry.:1 Introduction 1.1 Proton therapy 1.1.1 The beginnings 1.1.2 Essential features 1.1.3 Advantages and drawbacks 1.2 Range uncertainties and their consequences 1.3 Range verification methods 1.4 Prompt gamma-ray imaging 1.4.1 Passive collimation 1.4.2 Active collimation 1.4.3 Correlation to dose 1.5 Aim of this work 2 Compton camera 2.1 Theoretical background 2.1.1 Compton formula and Klein-Nishina cross section 2.1.2 Detection principle 2.1.3 Intersection of cone surface and plane 2.1.4 Practical considerations 2.2 Motivation 2.3 Goals 2.4 Materials 2.4.1 Scintillator properties 2.4.2 Block detector properties 2.4.3 Electronics and data acquisition 2.4.4 High efficiency Compton camera setup 2.5 Experimental setup 2.5.1 Accelerators 2.5.2 Detector setup 2.5.3 Trigger regime 2.6 Methods 2.6.1 Energy calibration 2.6.2 Spatial calibration 2.6.3 Time calibration 2.6.4 Error analysis 2.6.5 Systematic measurement program 2.7 Results – absorber choice 2.7.1 Energy resolution 2.7.2 Spatial resolution 2.7.3 Time resolution 2.8 Discussion – absorber choice 2.9 Results – BbCc setup 2.10 Discussion – BbCc setup 3 Prompt gamma-ray timing 3.1 Theoretical background 3.1.1 Detection principle 3.1.2 Kinematics 3.1.3 Detector model 3.1.4 Quantitative assessment 3.2 Goals 3.3 Materials 3.3.1 Detectors 3.3.2 Electronics 3.3.3 Accelerators 3.4 Methods 3.4.1 Detector and module settings 3.4.2 Proton bunch phase stability 3.4.3 Proton bunch time structure 3.4.4 Systematic measurement program 3.4.5 Data acquisition rate 3.4.6 Data analysis 3.4.7 Modelling of PGT spectra 3.5 Results 3.5.1 Intrinsic detector time resolution 3.5.2 Illustrative energy over time spectra 3.5.3 Proton bunch phase stability 3.5.4 Proton bunch time structure 3.5.5 Systematic measurement program 3.6 Discussion 3.7 Conclusions 4 Discussion 4.1 Detector load, event throughput and spot duration 4.2 Comparison of PGI systems 4.3 Summary 4.4 Zusammenfassung BibliographyBeschleunigte Protonen sind ausgezeichnete Kandidaten für die Behandlung von diversen Tumorarten. Diese geladenen Teilchen stoppen in einer bestimmten Tiefe, bei der die Ionisierungsdichte maximal ist. Da die deponierte Dosis hinter der distalen Kante sehr klein ist, minimiert die Protonentherapie den Schaden an normalem Gewebe verglichen mit der Photonentherapie. Inhärente Reichweitenunsicherheiten stellen jedoch die Bestrahlung von Tumoren in der Nähe von Risikoorganen in Frage und führen zur Anwendung von konservativen Sicherheitssäumen. Dadurch werden die potentiellen Vorteile der Protonen- gegenüber der Photonentherapie sowie ihre letzten Ziele eingeschränkt. Prompte Gammastrahlung, ein Nebenprodukt der Bestrahlung, welche mit der Dosisdeposition korreliert, ist eine zuverlässige Signatur um Reichweitenunterschiede zu detektieren und könnte sogar für eine dreidimensionale in vivo Dosimetrie genutzt werden. In dieser Arbeit werden zwei Methoden für Prompt Gamma-ray Imaging (PGI) erforscht: die Compton-Kamera (CK) und das Prompt Gamma-ray Timing (PGT)-Konzept. Des Weiteren soll deren Anwendbarkeit im klinischen Szenario diskutiert und verglichen werden. Die erste Methode strebt nach der Rekonstruktion der Emissionsdichtenverteilung der prompten Gammastrahlung und basiert auf einem iterativen Bildgebungsalgorithmus sowie auf mehreren positionsempfindlichen Detektoren. Diese werden in eine Streuer- und Absorberebene eingeteilt. Die zweite Methode ist vor Kurzem als eine Alternative zu kollimierten PGI Systemen vorgeschlagen worden, und beruht auf dem Prinzip der Zeitspektroskopie mit einem einzelnen monolithischen Detektor. Die Detektionszeiten der prompten Gammastrahlen beinhalten entscheidende Informationen über das Tiefendosisprofil aufgrund der messbaren Durchgangszeit von Ionen durch Materie. Am Helmholtz-Zentrum Dresden-Rossendorf (HZDR) und OncoRay werden Detektorkomponenten in realistischen Strahlungsumgebungen als ein Schritt zur klinischen CK charakterisiert. Konventionelle Blockdetektoren, welche in kommerziellen Positronen-Emissions-Tomographie (PET)-Scannern zum Einsatz kommen und auf Cer dotiertem Lutetiumoxyorthosilikat - Lu2SiO5:Ce (LSO) oder Bismutgermanat - Bi4Ge3O12 (BGO) Szintillatoren basieren, sind geeignete Kandidaten für den Absorber einer CK wegen der hohen Dichte und Absorptionseffizienz im Energiebereich von prompten Gammastrahlen (mehrere MeV). LSO- und BGO-Blockdetektoren werden in klinisch relevanten Strahlungsfeldern in Bezug auf Energie-, Orts- und Zeitauflösung verglichen. Weiterhin werden zwei BGO-Blockdetektoren (von PET-Scannern), angeordnet als BGO Block Compton-Kamera (BBCK), benutzt, um die Bildgebung von hochenergetischen prompten Gammastrahlen zu untersuchen, die in homogenen Plexiglas-Targets durch einen Protonen-Bleistiftstrahl emittiert werden. Die Motivation hierfür ist, die Detektionseffizienz der Streuerebene zu maximieren, wobei jedoch die Energieauflösung vernachlässigt wird. Targetverschiebungen, sowie Änderungen der Targetdicke und der Teilchenenergie werden untersucht. In einer Kollaboration zwischen OncoRay, HZDR and IBA, wird der erste Test des PGT-Konzepts an einem klinischen Protonenbeschleuniger (Westdeutsches Protonentherapiezentrum Essen) mit mehreren Detektoren und heterogenen Phantomen durchgeführt. Die Sensitivität der Methode hinsichtlich Reichweitenveränderungen wird erforscht. Des Weiteren wird der Einfluss von Untergrund und Stabilität des Zeitprofils des Strahlenbündels untersucht, sowie die Zeitverschmierung des Bündels für verschiedene Protonenenergien charakterisiert. Für die Materialauswahl für den Absorber der CK ergibt sich, dass sich BGO dem lichtstärkeren LSO Szintillator angleicht. Der Grund dafür sind die höheren Energien der prompten Gammastrahlung im Vergleich zum PET Szenario, welche die Energie-, Orts- und Zeitauflösung von BGO stark verbessern. Anhand von offensichtlichen Änderungen der Rückprojektionsbilder zeigt sich, dass mit der BBCK Verschiebungen einer punktförmigen radioaktiven Quelle erfolgreich detektiert, Linienquellen rekonstruiert und Verschiebungen der Protonenreichweite um einen Zentimeter identifiziert werden. Für die PGT-Experimente können mit einem einzigen Detektor Reichweitenunterschiede von fünf Millimetern für definierte heterogene Targets bei klinisch relevanten Dosen detektiert werden. Dies wird durch den numerischen Vergleich der Spektrumform ermöglicht. Bei größerer Ereigniszahl können Reichweitenunterschiede von bis zu zwei Millimetern detektiert werden. Die experimentellen Daten werden durch analytische Modellierung wiedergegeben. Die CK und das PGT-Konzept sind ambitionierte Ansätze zur Verifizierung der Reichweite in der Protonentherapie basierend auf PGI. Intensive Detektorcharakterisierung und Tests an klinischen Einrichtungen sind Pflicht für die Entwicklung geeigneter Prototypen, da der Energiebereich prompter Gammastrahlung sich über mehrere MeV erstreckt, was nicht dem Normbereich der traditionellen medizinischen Anwendungen entspricht. Im Bezug auf die Materialauswahl der CK wird ersichtlich, dass BGO trotz der allgemeinen Überlegenheit von LSO für die Anwendung im Bereich PGI aufholt. Wegen des niedrigeren Preises, der höheren Photoabsorptionseffizienz und der nicht vorhandenen Eigenaktivität erscheint BGO als eine konkurrenzfähige Alternative für die Absorberebene der CK im Vergleich zu LSO. Die Ergebnisse der BBCK, welche mit relativ einfachen Mitteln gewonnen werden, heben die potentielle Anwendung von Compton-Kameras für die Bildgebung prompter hochenergetischer Gammastrahlen hervor. Trotzdem stellen technische Beschränkungen wie die mangelnde Anzahl von Messereignissen pro Bestrahlungspunkt (falls klinische Ströme genutzt werden) die Anwendbarkeit der CK als Echtzeit- und in vivo Reichweitenverifikationsmethode in der Protonentherapie in Frage. Die PGT-Methode ist ein alternativer Ansatz, welcher aufgrund der geringeren Kosten und der höheren Effizienz eine schnellere Umsetzung in die klinische Praxis haben könnte. Ein Protonenbunchmonitor, höherer Detektordurchsatz und eine quantitative Reichweitenrekonstruktion sind die weiteren Schritte in Richtung eines klinisch anwendbaren Prototyps, der signifikante Reichweitenunterschiede für die stärksten Bestrahlungspunkte detektieren könnte. Die experimentellen Ergebnisse unterstreichen das Potential dieser Reichweitenverifikationsmethode an einem klinischen Bleistiftstrahl und lassen diesen neuartigen Ansatz als eine vielversprechende Alternative auf dem Gebiet der in vivo Dosimetrie erscheinen.:1 Introduction 1.1 Proton therapy 1.1.1 The beginnings 1.1.2 Essential features 1.1.3 Advantages and drawbacks 1.2 Range uncertainties and their consequences 1.3 Range verification methods 1.4 Prompt gamma-ray imaging 1.4.1 Passive collimation 1.4.2 Active collimation 1.4.3 Correlation to dose 1.5 Aim of this work 2 Compton camera 2.1 Theoretical background 2.1.1 Compton formula and Klein-Nishina cross section 2.1.2 Detection principle 2.1.3 Intersection of cone surface and plane 2.1.4 Practical considerations 2.2 Motivation 2.3 Goals 2.4 Materials 2.4.1 Scintillator properties 2.4.2 Block detector properties 2.4.3 Electronics and data acquisition 2.4.4 High efficiency Compton camera setup 2.5 Experimental setup 2.5.1 Accelerators 2.5.2 Detector setup 2.5.3 Trigger regime 2.6 Methods 2.6.1 Energy calibration 2.6.2 Spatial calibration 2.6.3 Time calibration 2.6.4 Error analysis 2.6.5 Systematic measurement program 2.7 Results – absorber choice 2.7.1 Energy resolution 2.7.2 Spatial resolution 2.7.3 Time resolution 2.8 Discussion – absorber choice 2.9 Results – BbCc setup 2.10 Discussion – BbCc setup 3 Prompt gamma-ray timing 3.1 Theoretical background 3.1.1 Detection principle 3.1.2 Kinematics 3.1.3 Detector model 3.1.4 Quantitative assessment 3.2 Goals 3.3 Materials 3.3.1 Detectors 3.3.2 Electronics 3.3.3 Accelerators 3.4 Methods 3.4.1 Detector and module settings 3.4.2 Proton bunch phase stability 3.4.3 Proton bunch time structure 3.4.4 Systematic measurement program 3.4.5 Data acquisition rate 3.4.6 Data analysis 3.4.7 Modelling of PGT spectra 3.5 Results 3.5.1 Intrinsic detector time resolution 3.5.2 Illustrative energy over time spectra 3.5.3 Proton bunch phase stability 3.5.4 Proton bunch time structure 3.5.5 Systematic measurement program 3.6 Discussion 3.7 Conclusions 4 Discussion 4.1 Detector load, event throughput and spot duration 4.2 Comparison of PGI systems 4.3 Summary 4.4 Zusammenfassung Bibliograph

Technological developments allowing for the widespread clinical adoption of proton radiotherapy

External beam radiation therapy using accelerated protons has undergone significant development since the first patients were treated with accelerated protons in 1954. Widespread adoption of proton therapy is now taking place and is fully justified based on early clinical and technical research and development. Two of the main advantages of proton radiotherapy are improved healthy tissue sparing and increased dose conformation. The latter has been improved dramatically through the clinical realization of Pencil Beam Scanning (PBS). Other significant advancements in the past 30 years have also helped to establish proton radiotherapy as a major clinical modality in the cancer-fighting arsenal. Proton radiotherapy technologies are constantly evolving, and several major breakthroughs have been accomplished which could allow for a major revolution in proton therapy if clinically implemented. In this thesis, I will present research and innovative developments that I personally initiated or participated in that brought proton radiotherapy to its current state as well as my ongoing involvement in leading research and technological developments which will aid in the mass adoption of proton radiotherapy. These include beam dosimetry, patient positioning technologies, and creative methods that verify the Monte Carlo dose calculations which are now used in proton treatment planning. I will also discuss major technological advances concerning beam delivery that should be implemented clinically and new paradigms towards patient positioning. Many of these developments and technologies can benefit the cancer patient population worldwide and are now ready for mass clinical implementation. These developments will improve proton radiotherapy efficiencies and further reduce the cost of proton therapy facilities. This thesis therefore reflects my historical and ongoing efforts to meet market costs and time demands so that the clinical benefit of proton radiotherapy can be realized by a more significant fraction of cancer patients worldwide

Design and Implementation of a High-Speed Readout and Control System for a Digital Tracking Calorimeter for proton CT

Particle therapy, a non-invasive technique for treating cancer using protons and light ions, has become more and more common. For example, a particle treatment facility is currently being built, in Bergen, Norway. Proton beams deposit a large fraction of their energy at the end of their paths, i.e., the delivered dose can be focused on the tumor, sparing nearby tissue with a low entry and almost no exit dose. A novel imaging modality using protons promises to overcome some limitations of particle therapy and allowing to fully exploit its potential. Being able to position the so-called Bragg peak accurately inside the tumor is a major advantage of charged particles, but incomplete knowledge about a crucial tissue property, the stopping power, limits its precision. A proton CT scanner provides direct information about the stopping power. It has the potential to reduce range uncertainties significantly, but no proton CT system has yet been shown to be suitable for clinical use. The aim of the Bergen proton CT project is to design and build a proton CT scanner that overcomes most of the critical limitations of the currently existing prototypes and which can be operated in clinical settings. A proton CT prototype, the Digital Tracking Calorimeter, is being developed as a range telescope consisting of high-granularity pixel sensors. The prototype is a combined position-sensitive detector and residual energy-range detector which will allow a substantial rate of protons, speeding up the imaging process. The detector is single-sided, meaning that it employs information from the beam delivery system to omit tracker layers in front of the phantom. The detector operates by tracking the charged particles traversing through the detector material behind the phantom. The proton CT prototype will be used to determine the feasibility of using proton CT to increase the dose planning accuracy for particle treatment of cancer cells. The detector is designed as a telescope of 43 layers of sensors, where the two front layers act as the position-sensitive detector providing an accurate vector of each incoming particle. The remaining layers are used to measure the residual energy of each particle by observing in which layer they stop and by using the cluster size in each layer. The Digital Tracking Calorimeter employs the ALPIDE sensor, a monolithic active pixel sensor, each utilizing a 1.2Gb/s data link. Each layer of 18×27 cm consists of 108 ALPIDE sensors, roughly corresponding to the width and height of the head of a grown person. The sensors are connected to intermediary transition boards that route the data and control links to dedicated readout electronics and supply the sensors with power. The readout unit is the main component of both the data acquisition and the detector control system. The power control unit controls the power supply and monitors the current usage of the sensors. Both of these devices are mainly implemented in FPGAs. The main purpose of this work has been to explore and implement possible design solutions for the proton CT electronics, including the front-end, as well as the readout electronics architecture. The resulting architecture is modular, allowing the further scale-up of the system in the future. A major obstacle to the design is the high amount of sensors and the corresponding high-speed data links. Thus, a large emphasis has been on the signal integrity of the front-end electronics and a dynamic phase alignment sampling method of the readout electronics firmware. The readout FPGA employs regular I/O pins for the high-speed data interface, instead of high-speed transceiver pins, which significantly reduces the magnitude of the data acquisition system. A consistent design approach with detailed and systematic verification of the FPGA firmware modules, along with a continuous integration build system, has resulted in a stable and highly adaptive system. Significant effort has been put into the testing of the various system components. This also includes the design and implementation of a set of production test tools for use during the manufacturing of the detector front-end.Doktorgradsavhandlin