This thesis has contributed to the achievement of in-beam PET as a promising clinical monitoring technique. In response to a pressing medical demand, this work has provided a tool for quantification of local dose deviations in case of observed discrepancies between the measured and expected PET images. The implemented interactive approach described in chapter 3 is in clinical use since 2001. It provides the radio-oncologist with a valuable feedback which may allow a prompt reaction in the strategy of the therapy prior to the delivery of the successive treatment fraction in case of significant deviations between planned and actually applied dose. ...

This thesis has contributed to the achievement of in-beam PET as a promising clinical monitoring technique. In response to a pressing medical demand, this work has provided a tool for quantification of local dose deviations in case of observed discrepancies between the measured and expected PET images. The implemented interactive approach described in chapter 3 is in clinical use since 2001. It provides the radio-oncologist with a valuable feedback which may allow a prompt reaction in the strategy of the therapy prior to the delivery of the successive treatment fraction in case of significant deviations between planned and actually applied dose. ...

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Charged particle beams are an increasingly common method of cancer treatment. Because of their Bragg peak dose distribution, protons are an effective way to deliver a dose to the tumor, while minimizing the dose to surrounding tissue. Charged particles with greater mass and higher charge than protons have an even sharper Bragg peak and a higher Relative Biological Effectiveness (RBE), allowing a greater dose to be delivered to the tumor and sparing healthy tissue. Since carbon ions are being implemented for treatment in Europe and Japan, this study will focus on carbon as the heavier ion of choice. Comparisons are drawn between moderated and unmoderated protons and carbon ions, all of which have a penetration depth of 10 cm in tissue. Scattering off the beam line, dose delivered in front of and behind the tumor, and overall dose mapping are examined, along with fragmentation of the carbon ions. It was found that fragmentation of the carbon ion beam introduced serious problems in terms of controlling the dose distribution. The dose to areas behind the tumor was significantly higher for carbon ions versus proton beams. For both protons and carbon ions, the use of a moderator increased the scattering off of the beam line, and slightly increased the dose behind the tumor. For carbon ions, the use of a moderator increased the degree of fragmentation throughout the beam path.

In-beam positron emission tomography (in-beam PET) is currently the only method for an in-situ monitoring of highly tumor-conformed charged hadron therapy. In such therapy, the clinical effect of deviations from treatment planning is highly minimized by implementing safety margins around the tumor and selecting proper beam portals. Nevertheless, in-beam PET is able to detect eventual, undesirable range deviations and anatomical modifications during fractionated irradiation, to verify the accuracy of the beam portal delivered and to provide the radiotherapist with an estimation of the difference in dosage if the treatment delivered differs from the planned one. In a first study within this work, a set of simulation and fully-3D reconstruction routines shows that minimizing the opening angle of a cylindrical camera is determinant for an optimum quality of the in-beam PET images. The study yields two favorite detector geometries: a closed ring or a dual-head tomograph with narrow gaps. The implementation of either detector geometry onto an isocentric, ion beam delivery (gantry) is feasible by mounting the PET scanner at the beam nozzle. The implementation of an in-beam PET scanner with the mentioned detector geometries at therapeutic sites with a fixed, horizontal beam line is also feasible. Nevertheless, knowing that previous in-beam PET research in Berkeley was abandoned due to detector activation (Bismuth Germanate, BGO), arising most probably from passive beam shaping contaminations, the proposed detector configurations had to be tested in-beam. For that, BGO was substituted with a state-of-the-art scintillator (lutetium oxyorthosilicate, LSO) and two position sensitive detectors were built. Each detector contains 32 pixels, consisting of LSO finger-like crystals coupled to avalanche photodiode arrays (APDA). In order to readout the two detectors operated in coincidence, either in standalone mode or at the GSI medical beam line, a multi-channel, zero-suppressing free, list mode data acquisition system was built.The APDA were chosen for scintillation detection instead of photomultiplier tubes (PMT) due to their higher compactness and magnetic field resistance. A magnetic field resistant detector is necessary if the in-beam PET scanner is operated close to the last beam bending magnet, due to its fringe magnetic field. This is the case at the isocentric, ion beam delivery planned for the dedicated, heavy ion hospital facility under construction in Heidelberg, Germany. In-beam imaging with the LSO/APDA detectors positioned at small target angles, both upbeam and downbeam from the target, was successful. This proves that the detectors provide a solution for the proposed next-generation, improved in-beam PET scanners. Further confirming this result are germanium-detector-based, spectroscopic gamma-ray measurements: no scintillator activation is observed in patient irradiation conditions. Although a closed ring or a dual-head tomograph with narrow gaps is expected to provide improved in-beam PET images, low count rates in in-beam PET represent a second problem to image quality. More importantly, new accelerator developments will further enhance this problem to the point of making impossible in-beam PET data taking if the present acquisition system is used. For these reasons, two random-suppression methods allowing to collect in-beam PET events even during particle extraction were tested. Image counts raised almost twofold. This proves that the methods and associated data acquisition technique provide a solution for next-generation, in-beam positron emission tomographs installed at synchrotron or cyclotron radiotherapy facilities.

Background: Current studies in radiotherapy aim to develop better methods for curing patients fromcancer. Since different types of radiation interact with biological matter in various ways, the resultsof their interaction and their effectiveness with respect to the biological damage to cells have ageneral investigation interest. Aim: The work in this project aims to use a mathematical model to fit a pre-existing data onclonogenic survival of cells irradiated by different types of radiation and report the fittingparameters. Various radiobiological concepts were investigated and compared between differentradiation qualities used in this work. Materials and Methods: The repairable-conditionally repairable (RCR) damage model parametrisedwith respect to the linear energy transfer (LET) of the cell oxygenation was used for fittingexperimental cell survival data for human salivary gland cells irradiated in oxic and hypoxicconditions with protons, 12C-, 20Ne- and 3He-ions. Results: Good consistency with the entire cell survival data was achieved. RCR-model was robustenough to achieve agreement with cell survival data for LET values excluded from fitting procedure.Slope of cell survival curves for the three ions increased up to optimal LET value reaching maximumthere and it decreased at higher LETs. RBE of 3He-ions showed the most rapid increase in low-LETregion and reached a higher maximum as compared with other ions. RBE of the three ions increasedapproximately in the same LET region as a and c parameters of RCR-model, but no underlyingradiobiological mechanism could explain any of curve shape similarities. The RBE of 12C-ions reachedmaximum approximately at 126 keV/μm, which is the optimal LET that could possibly correspond tothe steepest cell survival curve. It was observed how the cell oxygenation became less important forcell irradiation with very high LET values. Conclusion: The results showed that it is feasible to use the RCR model to fit the broad range of cellsurvival curves corresponding to different radiation qualities and the assessment of their relativebiological effectiveness in oxic and hypoxic irradiation conditions. RCR-model may have a possible application in cell irradiation with other ion beams than those used in this work.

In-beam positron emission tomography (in-beam PET) is currently the only method for an in-situ monitoring of highly tumor-conformed charged hadron therapy. In such therapy, the clinical effect of deviations from treatment planning is highly minimized by implementing safety margins around the tumor and selecting proper beam portals. Nevertheless, in-beam PET is able to detect eventual, undesirable range deviations and anatomical modifications during fractionated irradiation, to verify the accuracy of the beam portal delivered and to provide the radiotherapist with an estimation of the difference in dosage if the treatment delivered differs from the planned one. In a first study within this work, a set of simulation and fully-3D reconstruction routines shows that minimizing the opening angle of a cylindrical camera is determinant for an optimum quality of the in-beam PET images. The study yields two favorite detector geometries: a closed ring or a dual-head tomograph with narrow gaps. The implementation of either detector geometry onto an isocentric, ion beam delivery (gantry) is feasible by mounting the PET scanner at the beam nozzle. The implementation of an in-beam PET scanner with the mentioned detector geometries at therapeutic sites with a fixed, horizontal beam line is also feasible. Nevertheless, knowing that previous in-beam PET research in Berkeley was abandoned due to detector activation (Bismuth Germanate, BGO), arising most probably from passive beam shaping contaminations, the proposed detector configurations had to be tested in-beam. For that, BGO was substituted with a state-of-the-art scintillator (lutetium oxyorthosilicate, LSO) and two position sensitive detectors were built. Each detector contains 32 pixels, consisting of LSO finger-like crystals coupled to avalanche photodiode arrays (APDA). In order to readout the two detectors operated in coincidence, either in standalone mode or at the GSI medical beam line, a multi-channel, zero-suppressing free, list mode data acquisition system was built.The APDA were chosen for scintillation detection instead of photomultiplier tubes (PMT) due to their higher compactness and magnetic field resistance. A magnetic field resistant detector is necessary if the in-beam PET scanner is operated close to the last beam bending magnet, due to its fringe magnetic field. This is the case at the isocentric, ion beam delivery planned for the dedicated, heavy ion hospital facility under construction in Heidelberg, Germany. In-beam imaging with the LSO/APDA detectors positioned at small target angles, both upbeam and downbeam from the target, was successful. This proves that the detectors provide a solution for the proposed next-generation, improved in-beam PET scanners. Further confirming this result are germanium-detector-based, spectroscopic gamma-ray measurements: no scintillator activation is observed in patient irradiation conditions. Although a closed ring or a dual-head tomograph with narrow gaps is expected to provide improved in-beam PET images, low count rates in in-beam PET represent a second problem to image quality. More importantly, new accelerator developments will further enhance this problem to the point of making impossible in-beam PET data taking if the present acquisition system is used. For these reasons, two random-suppression methods allowing to collect in-beam PET events even during particle extraction were tested. Image counts raised almost twofold. This proves that the methods and associated data acquisition technique provide a solution for next-generation, in-beam positron emission tomographs installed at synchrotron or cyclotron radiotherapy facilities.

Das Hauptziel einer Strahlentherapie, die möglichst vollständige Vernichtung des Tumorgewebes bei einer höchstmöglichen Schonung des umliegenden Gewebes und der Risikoorgane, kann mit Kohlenstoffionen besser als mit Elektronen oder Gammastrahlung erreicht werden. Ionen haben ein inverses Tiefen-Dosisprofil, sie geben einen Großteil ihrer Energie am Ende ihres Weges durch Materie ab. Dieses Energieabgabeverhalten, die wohl definierte Reichweite und die erhöhte biologische Wirksamkeit im Tumor prädestinieren zum Beispiel Kohlenstoffionen für die Behandlung inoperabler, gegen konventionell eingesetzte Strahlung resistenter Tumoren. Allerdings führen diese Eigenschaften der Strahlung auch dazu, dass Veränderungen der Dichte der Materie im Strahlweg zu einer Verschiebung des Maximums der Energieabgabe und damit zu einer deutlichen Veränderung der Dosisverteilung führen. Ein Monitoring der reichweitesensitiven Ionenbestrahlungen ist somit erforderlich. Die Positronen-Emissions-Tomographie (PET), die normalerweise dazu benutzt wird, die Verteilung eines injizierten Positronenemitters im Gewebe zu bestimmen, kann hier eingesetzt werden. Durch Kernreaktionen der einfliegenden Kohlenstoffionen mit Atomkernen des Gewebes kommt es zur Erzeugung von Positronenemittern, die über ihren Zerfall mit dem an der experimentellen Therapieanlage an der Gesellschaft für Schwerionenforschung installierten in-beam PET-Scanner nachgewiesen werden können. Da die Dosisverteilung und die erzeugte Aktivitätsverteilung durch verschiedene physikalische Prozesse bedingt sind, ist ein direkter Vergleich der PET-Messung mit der von den Ärzten und Medizinphysikern festgelegten Dosisverteilung nicht möglich. Aus der Dosisverteilung und dem Zeit-ablauf der Bestrahlung wird eine Vorhersage der Aktivitätsverteilung berechnet, die dann mit der Messung verglichen wird. Auf der Grundlage dieses Vergleiches ist die in-beam PET-Methode in der Lage, während der Behandlung Reichweiteabweichungen im Patienten, Ungenauigkeiten in der Positionierung und auch Fehler im physikalischen Strahlmodell aufzuzeigen. Trotz einer guten Anpassung der in der Vorausberechnung verwendeten physikalischen Modelle an die Realität kommt es zu Abweichungen, die nicht mit einer ungenauen Dosisapplikation begründbar sind. Diese sind zum größten Teil durch die metabolischen Vorgänge im Patienten bedingt, an denen die Positronenemitter teilnehmen. Diese Washout-Prozesse sind zwischen verschiedenen Patienten und verschiedenen Behandlungstagen nicht reproduzierbar. Im Rahmen der vorliegenden Arbeit wurde eine Quantifizierung des Washouts in Abhängigkeit verschiedener Parameter vorgenommen, deren Berücksichtigung zur Verbesserung der Vorausberechnung führt. Um eine flexiblere Positionierung des Patienten am raumfesten Bestrahlungssystem der GSI zu ermöglichen, wurde an der GSI ein Bestrahlungsstuhl entwickelt. Um auch bei der Bestrahlung sitzender Patienten eine in-beam PET-Messung zu ermöglichen, sind die beiden Detektor-Einheiten der PET-Kamera um die Strahlachse drehbar. Durch die hohe Eigenmasse der Detektoren kommt es jedoch zu Deformationen der idealen Kreisbahn. Um eine ortsgenaue Rekonstruktion der Daten zu ermöglichen, müssen diese Deformationen quantifiziert und korrigiert werden. Dies war ein weiteres Anliegen dieser Arbeit. Das wichtigste Ziel der vorliegenden Dissertation jedoch war, die in-beam PET-Methode auf neue Ionensorten zu erweitern. Es wurde gezeigt, dass die in-beam PET-Methode auch für 3He-Bestrahlungen angewendet werden kann. Dafür wurden Experimente an einem 3He-Strahl durchgeführt. Die Aktivitätsausbeute ist bei gleicher applizierter Dosis etwa dreimal so hoch wie bei 12C-Bestrahlungen. Die erreichbare Reichweite-Auflösung ist kleiner als 1 mm. Bei der Bestrahlung eines inhomogenen Phantoms wurde gezeigt, dass ein Kontrast zwischen verschiedenen Materialien auflösbar ist. Aus den experimentell bestimmten Reaktionsraten wurden Wirkungsquerschnitte für zu Positronenemittern führende Reaktionen abgeschätzt. Die in den 3He-Experimenten genommenen Daten wurden denen in Kohlenstoff-Ionen-Experimenten gewonnen sowie Literaturdaten für Protonenbestrahlungen gegenübergestellt. Ein Vergleich mit den Rechnungen des Simulationsprogrammes Shield-Hit erfolgte. Eine Zusammenstellung von Wirkungsquerschnittsmodellen und die aufgestellten Anforderungen an ein für in-beam PET verwendbares Simulationsprogramm sind vorbereitend für weitere Arbeiten.

In radiotherapy, a quantity asked for by clinics when calculating a treatment plan, along withdose, is linear energy transfer. Linear energy transfer is defined as the absorbed energy intissue per particle track length and has been shown to increase with relative biologicaleffectiveness untill the overkilling effect. In this master thesis the dose averaged linear energytransfer from proton and carbon ion beams was simulated using the FLUKA multi purposeMonte Carlo code. The simulated distributions have been compared to algorithms fromRaySearch Laboratories AB in order to investigate the agreement between the computationmethods. For the proton computation algorithm improvements to the current scoring algorithmwere also implemented. A first version of the linear energy transfer validation code was alsoconstructed. Scoring of linear energy transfer in the RaySearch algorithm was done with theproton Monte Carlo dose engine and the carbon pencil beam dose engine. The results indicatedthat the dose averaged linear energy transfer from RaySearch Laboratories agreed well for lowenergies for both proton and carbon beams. For higher energies shape differences were notedwhen using both a small and large field size. The protons, the RaySearch algorithm initiallyoverestimates the linear energy transfer which could result from fluence differences in FLUKAcompared to the RaySearch algorithm. For carbon ions, the difference could stem from someloss of information in the tables used to calculate the linear energy transfer in the RaySearchalgorithm. From validation γ-tests the proton linear energy transfer passed for (3%/3mm) and(1%/1mm) with no voxels out of tolerance. γ-tests for the carbon linear energy transfer passedwith no voxels out of tolerance for (5%/5mm) and a fail rate of 2.92% for (3%/3mm).