The goal of this research is to evaluate the secondary prompt gamma (PG) yield from proton therapy at high characteristic energies from MC model simulations and experimental data. Recent studies indicate that target composition influences PG characteristic energy and yield, and the quantification of PG may be used to offer real-time dose verification for proton therapy. In this study PG analysis was performed for MC simulations to evaluate the characteristic measurements and total yield of secondary PG emitted from a target in the 0-8 MeV range from a proton therapy beam over a range of four different beam energies (70 MeV, 160 MeV, 200 MeV, 220 MeV). This was repeated in several target materials (carbon, calcium oxide, calcium fluoride, PMMA, and HDPE) in order to evaluate the influence of the incident energy and the target material on the PG yield and energy spectra. PG energy spectra determined from the specified target materials indicated that the 3.74 MeV energy peak shows a linear correlation between PG intensity and calcium mass fraction of the target material. 6.13 MeV and 4.44 MeV energy peak are not unique to the respective, oxygen and combined oxygen and carbon, mass fraction of the target material. This relationship is complicated by the addition of calcium within the target. Experimental data was collected in order to validate the computational model based on comparison of relative characteristic energy peek intensities. The relative peak ratio determined from experimental data is in good agreement with model prediction, the combined peak ratio is within 0.2%.

A prompt-gamma, neutron-activation analysis facility earlier developed at the Nuclear Science Center of Texas A&M University could not be used successfully to analyze geologic samples due to high detection background, low neutron fluence rate and poor detection equipment . A systematic investigation into the performance capability of a prompt-gamma, neutron activation analysis facility was undertaken in this research project. The facility was reconstructed and used to obtain prompt-gamma spectra of chlorine and cadmium and from the spectra, the net peak area counts for the most intense prompt-gamma-ray energies were obtained. A theoretical model was developed which can predict the net peak area counts expected on these prompt-gamma-ray energies using the thermal neutron fluence rate at the sample position, the absolute efficiency of the detector, and the mass and partial gamma-ray production cross section data for the samples. The experimental and predicted results were compared to establish the performance capability of the reconstructed facility. Good agreements between experimental and predicted results were obtained for chlorine, but results from cadmium showed larger discrepancies due to self-shielding effects. Corrections for self-shielding effects were applied to results from cadmium and the experimental and predicted results were also in good agreement. The satisfactory results indicate that it is possible to implement the prompt-gamma, neutron-activation analysis technique at Beam Port #1 of the Nuclear Science Center Reactor. To be able to obtain excellent results from other samples, improvements in shielding materials to attain a lower detection background and a highly efficient detection system should be incorporated.

A prompt-gamma, neutron-activation analysis facility earlier developed at the Nuclear Science Center of Texas A&M University could not be used successfully to analyze geologic samples due to high detection background, low neutron fluence rate and poor detection equipment . A systematic investigation into the performance capability of a prompt-gamma, neutron activation analysis facility was undertaken in this research project. The facility was reconstructed and used to obtain prompt-gamma spectra of chlorine and cadmium and from the spectra, the net peak area counts for the most intense prompt-gamma-ray energies were obtained. A theoretical model was developed which can predict the net peak area counts expected on these prompt-gamma-ray energies using the thermal neutron fluence rate at the sample position, the absolute efficiency of the detector, and the mass and partial gamma-ray production cross section data for the samples. The experimental and predicted results were compared to establish the performance capability of the reconstructed facility. Good agreements between experimental and predicted results were obtained for chlorine, but results from cadmium showed larger discrepancies due to self-shielding effects. Corrections for self-shielding effects were applied to results from cadmium and the experimental and predicted results were also in good agreement. The satisfactory results indicate that it is possible to implement the prompt-gamma, neutron-activation analysis technique at Beam Port #1 of the Nuclear Science Center Reactor. To be able to obtain excellent results from other samples, improvements in shielding materials to attain a lower detection background and a highly efficient detection system should be incorporated.

Ce travail de thèse a été effectué dans le cadre de la collaboration CLaRyS, qui a pour objectif le développement d'une caméra gamma multi-collimatée et d'une caméra Compton pour les applications médicales notamment pour le contrôle en ligne de l’hadronthérapie. La caméra Compton pourrait également être utilisée en médecine nucléaire. L’objectif principal de ce travail de thèse était la caractérisation complète des détecteurs qui composent les caméras et le test des deux systèmes complets avec des faisceaux d’ions cliniques. En parallèle, des études en simulation ont permis d'estimer les performances de la caméra Compton à la fois pour le contrôle de l’hadronthérapie et la médecine nucléaire / This thesis work has been carried out within the CLaRyS French collaboration, which is involved in the development of a multi-collimated gamma camera and a Compton camera for the application in ion beam therapy monitoring through prompt-gamma detection and in nuclear medicine examinations. The main goal of the thesis was the complete characterization of the camera detector components, and the test of the whole systems on clinical ion beams. In parallel, simulation works have been performed to assess the performance of the Compton camera for the measurement of ion range during proton and carbon therapy, and for single photon emission computed tomography application in the nuclear medicine field

The prompt gamma-ray timing (PGT) method offers a relatively simple approach for range verification in proton therapy. Starting from the findings of previous experiments, several steps toward a clinical application of PGT have been performed in this work. First of all, several scintillation materials have been investigated in the context of PGT. The time resolution was determined at high photon energies in the MeV-region. In conclusion, the fast and bright scintillator CeBr3 is the material of choice in combination with a timing photomultiplier tube as light detector. A second study was conducted at Universitäts Protonen Therapie Dresden (UPTD) to characterize the proton bunch structure of a clinical beam concerning its time width and relative arrival time. The data is mandatory as input for simulation studies and to correct for phase drifts. The obtained data could furthermore be used for the first 2D imaging of a heterogeneous phantom based on prompt gamma-rays. In a last step, a PGT prototype system was designed using the findings from the first two studies. The prototype system is based on a newly developed digital spectrometer and a CeBr3 detector. The device is characterized at the ELBE bremsstrahlung beam. It was verified that the prototype operates within the specifications concerning time and resolution as well as throughput rate. Finally, for the first time the PGT system was used under clinical conditions in the treatment room of UPTD. Here, PGT data was obtained from the delivery of a three-dimensional treatment plan onto PMMA phantoms. The spot-by-spot analysis helped to investigate the performance of the prototype device under clinical conditions. As a result, range variations of 5 mm could be detected for the first time with an uncollimated system at clinically relevant doses. To summarize, the obtained results help to bring PGT closer to a clinical application.

samples were irradiated for approximately 45 minutes to allow for the saturation of fission products. The first method used the beam port shutter and allowed for longer counting and irradiation times, but was unsuitable for examining fission products with half-lives below 10 seconds. The on/off method used a cycle of equal irradiation and counting times of one minute. The second method is able to measure track the production of fission products with half-lives of less than 10 seconds. This method used a borated aluminum wheel beam chopper to stop the irradiation of the sample during counting. The beam chopper was set to cycle for approximately one second of counting following half a second of irradiation. The spectra from both methods were analyzed and the peaks were assigned to the appropriate fission products. The majority of the peaks were composed of gamma-rays from multiple nuclides. The peaks created by gamma-rays from decays of a single nuclide were used to calculate the detection limits of the system. Using the beam chopper system, 21 peaks would be above the detection limits of our system 95% of the time for uranium samples of less than one kilogram. / text

Accurate estimates for the molecular transport coefficients are critical to predicting the movement of gases in geological media. Here I present a novel methodology for using prompt gamma activation analysis to measure the effective diffusivity of noble gases in a porous medium. I also present a model to estimate the connectivity parameter of a soil from measurements of its saturated conductivity, macro porosity, and pore volume and pore surface fractal dimensions. Experiments with argon or xenon diffusing through a nitrogen saturated geological media were conducted. The noble gas concentration variations at its source were measured using prompt gamma activation analysis and later compared to a numerical diffusion model to estimate the effective diffusion coefficient. Numerical simulations using the estimated diffusivity and the experimental argon data produced results with a correlation parameter R² = 0.98. However, neglecting transport mechanisms other than diffusion largely under-predicted the xenon depletion rates observed during the first hours of experiment. To explain these results, a second model was developed which included the effect of pressure gradients and bulk convection that might arise from the faster molecular migration of the light species in a non-equimolar system and gravitational currents. Finally, the fractal model developed for this dissertation was used to estimate the connectivity parameters and walking fractal dimension of a group of geological samples that were previously characterized. This model successfully predicted positive connectivity factors and walking fractal dimensions between two and three for every sample analyzed. / text

The prompt gamma-ray timing (PGT) method offers a relatively simple approach for range verification in proton therapy. Starting from the findings of previous experiments, several steps toward a clinical application of PGT have been performed in this work. First of all, several scintillation materials have been investigated in the context of PGT. The time resolution was determined at high photon energies in the MeV-region. In conclusion, the fast and bright scintillator CeBr3 is the material of choice in combination with a timing photomultiplier tube as light detector. A second study was conducted at Universitäts Protonen Therapie Dresden (UPTD) to characterize the proton bunch structure of a clinical beam concerning its time width and relative arrival time. The data is mandatory as input for simulation studies and to correct for phase drifts. The obtained data could furthermore be used for the first 2D imaging of a heterogeneous phantom based on prompt gamma-rays. In a last step, a PGT prototype system was designed using the findings from the first two studies. The prototype system is based on a newly developed digital spectrometer and a CeBr3 detector. The device is characterized at the ELBE bremsstrahlung beam. It was verified that the prototype operates within the specifications concerning time and resolution as well as throughput rate. Finally, for the first time the PGT system was used under clinical conditions in the treatment room of UPTD. Here, PGT data was obtained from the delivery of a three-dimensional treatment plan onto PMMA phantoms. The spot-by-spot analysis helped to investigate the performance of the prototype device under clinical conditions. As a result, range variations of 5 mm could be detected for the first time with an uncollimated system at clinically relevant doses. To summarize, the obtained results help to bring PGT closer to a clinical application.

Die Protonentherapie zeichnet sich durch eine konformale und fokussierte Tumorbestrahlung aus, die es ermöglicht, gesundes Gewebe besser zu schonen als bei der konventionellen Strahlentherapie. Dieses Potential wird jedoch durch Unsicherheiten bei der Vorhersage der Protonenreichweite im Gewebe oder durch anatomische Veränderungen über den Verlauf der Therapie eingeschränkt. In der vorliegenden Arbeit wurde daher der klinische Nutzen eines Reichweiteverifikationssystems auf Grundlage von Prompt-Gamma-Imaging (PGI) zur Behandlungskontrolle untersucht. Dafür wurden Messungen mit einem PGI-System während Prostata- und Kopf-Hals-Tumor-Bestrahlungen durchgeführt und retrospektiv ausgewertet. Einerseits konnte dabei mittels PGI die Genauigkeit verschiedener Methoden zur Reichweitevorhersage überprüft werden. Es zeigte sich, dass die 2019 klinisch eingeführte Methode zur Reichweitevorhersage (DirectSPR) nicht von der mit PGI gemessenen Protonenreichweite in Prostata-Tumor-Bestrahlungen abweicht, wodurch die Reduktion der auf DirectSPR basierenden Reichweiteunsicherheiten unabhängig bestätigt werden konnte. Andererseits konnte die Detektionsfähigkeit von PGI bei der Erkennung relevanter und nicht relevanter anatomischer Veränderungen in applizierten Bestrahlungsfeldern nachgewiesen werden. Insbesondere wurde für die feldweise Klassifizierung der Prostata-Bestrahlungen eine Sensitivität und Spezifität von 74% bzw. 79% festgestellt. Damit konnte in dieser Dissertation erstmals systematisch das klinische Anwendungspotential eines Systems zur PGI-Reichweiteverifikation gezeigt werden. Als zusätzliche Untersuchung wurde in einer Kollaboration mit dem Massachusetts General Hospital zum ersten Mal ein Vergleich zwischen zwei verschiedenen, auf prompter Gammastrahlung basierenden Systemen zur Reichweiteverifikation durchgeführt. Dazu wurde ein standardisiertes Studienprotokoll etabliert, welches die Vergleichbarkeit und die klinische Implementierung von Reichweiteverifikationssystemen generell unterstützen könnte.:1 Einleitung 2 Strahlentherapie mit Protonen 2.1 Physikalische Grundlagen der Protonentherapie 2.2 Behandlungsablauf in der Protonentherapie 2.2.1 Bildgebung zur Therapieplanung 2.2.2 Bestrahlungsplanung 2.2.3 Strahlapplikation 2.3 Genauigkeit in der Protonentherapie 2.3.1 Ursachen für Behandlungs- und Reichweiteunsicherheiten 2.3.2 Aktueller Stand der Behandlungs- und Reichweiteverifikation 3 Methodik der Reichweiteverifikation mittels Prompt-Gamma-Bildgebung (PGI) 3.1 Funktionsprinzip der PGI-Schlitzkamera 3.2 Datenaufnahme und -verarbeitung 3.2.1 Detektoraufbau und Signalaufnahme 3.2.2 PGI-Simulation und Bestimmung der Reichweiteabweichung 3.3 Charakterisierung des PGI-Prototyps 3.3.1 Kalibrierung des Systems 3.3.2 Positionierungspräzision 3.4 Überblick zur PRIMA-Studie 3.5 Experimentelle Studien zur PGI-Simulationsgenauigkeit 3.5.1 Abhängigkeit vom PGI-Sichtfeld und der Protonenenergie 3.5.2 Validierung der erweiterten Simulationssoftware 3.5.3 Abhängigkeit von der Tumorentität 3.5.4 Schlussfolgerungen 4 Validierung der CT-basierten Reichweitevorhersage mittels PGI 4.1 Konzept der Validierung 4.2 Gesamtabschätzung der Validierungsunsicherheit 4.3 Ergebnisse der Validierung 4.4 Diskussion 5 Detektionsfähigkeit anatomischer Veränderungen mittels PGI 5.1 Prinzipieller Aufbau der Studie 5.2 Grundwahrheit auf Basis von CT- und Dosisinformationen 5.2.1 Manuelle Klassifizierung 5.2.2 Klassifizierung auf Grundlage von integrierten Tiefendosisprofilen 5.2.3 Ergebnis der Etablierung einer CT-basierten Grundwahrheit 5.3 Etablierung einer Klassifikation auf Basis von PGI-Daten 5.3.1 Verarbeitung der PGI-Daten mittels Cluster-Algorithmus 5.3.2 Definition von spot- oder clusterbasierten Klassifikationsmodellen 5.4 Ergebnisse der PGI-Detektionsfähigkeit 5.4.1 Auswertung für Patienten mit Prostata-Tumor 5.4.2 Auswertung für Patienten mit Tumoren im Kopf-Hals-Bereich 5.5 Diskussion 6 Genauigkeit zweier Reichweiteverifikationsmethoden – bizentrischer Vergleich 6.1 Material und Methoden 6.1.1 Bildgebung 6.1.2 Bestrahlungsplanung 6.1.3 Durchführung und Auswertung 6.2 Ergebnisse 6.3 Diskussion 7 Zusammenfassung 8 Summary / Proton therapy is a conformal and focused irradiation of the tumor, which allows for a better sparing of healthy tissue than with conventional radiotherapy. However, this potential is limited by uncertainties from the proton range prediction in the patient or anatomical changes over the course of the treatment. Therefore, in this work, the clinical benefit of a range verification system based on the prompt-gamma-imaging (PGI) method for treatment verification was investigated. For this purpose, measurements were carried out with a PGI system during prostate and head and neck cancer irradiations and evaluated retrospectively. On the one hand, PGI was used to review the accuracy of several range prediction methods. The results showed that a specific method for range prediction (DirectSPR), which was clinically introduced in 2019, does not deviate from the PGI-measured proton range in prostate cancer irradiations. This means that the reduction of the range uncertainties with DirectSPR could be independently confirmed. On the other hand, the detection capability of PGI in identifying relevant and non-relevant anatomical changes in delivered treatment fields was demonstrated. In particular, for the fieldwise classification of prostate irradiations a sensitivity and specificity of 74% and 79% was determined, respectively. Thus, the clinical potential of a PGI range verification system was for the first time systematically demonstrated in this thesis. Furthermore, in a collaboration with the Massachusetts General Hospital a first-time comparison of two different range verification systems based on prompt gamma radiation was conducted. Therefore, a standardized study protocol was established, which could generally foster the comparability and clinical implementation of range verification systems.:1 Einleitung 2 Strahlentherapie mit Protonen 2.1 Physikalische Grundlagen der Protonentherapie 2.2 Behandlungsablauf in der Protonentherapie 2.2.1 Bildgebung zur Therapieplanung 2.2.2 Bestrahlungsplanung 2.2.3 Strahlapplikation 2.3 Genauigkeit in der Protonentherapie 2.3.1 Ursachen für Behandlungs- und Reichweiteunsicherheiten 2.3.2 Aktueller Stand der Behandlungs- und Reichweiteverifikation 3 Methodik der Reichweiteverifikation mittels Prompt-Gamma-Bildgebung (PGI) 3.1 Funktionsprinzip der PGI-Schlitzkamera 3.2 Datenaufnahme und -verarbeitung 3.2.1 Detektoraufbau und Signalaufnahme 3.2.2 PGI-Simulation und Bestimmung der Reichweiteabweichung 3.3 Charakterisierung des PGI-Prototyps 3.3.1 Kalibrierung des Systems 3.3.2 Positionierungspräzision 3.4 Überblick zur PRIMA-Studie 3.5 Experimentelle Studien zur PGI-Simulationsgenauigkeit 3.5.1 Abhängigkeit vom PGI-Sichtfeld und der Protonenenergie 3.5.2 Validierung der erweiterten Simulationssoftware 3.5.3 Abhängigkeit von der Tumorentität 3.5.4 Schlussfolgerungen 4 Validierung der CT-basierten Reichweitevorhersage mittels PGI 4.1 Konzept der Validierung 4.2 Gesamtabschätzung der Validierungsunsicherheit 4.3 Ergebnisse der Validierung 4.4 Diskussion 5 Detektionsfähigkeit anatomischer Veränderungen mittels PGI 5.1 Prinzipieller Aufbau der Studie 5.2 Grundwahrheit auf Basis von CT- und Dosisinformationen 5.2.1 Manuelle Klassifizierung 5.2.2 Klassifizierung auf Grundlage von integrierten Tiefendosisprofilen 5.2.3 Ergebnis der Etablierung einer CT-basierten Grundwahrheit 5.3 Etablierung einer Klassifikation auf Basis von PGI-Daten 5.3.1 Verarbeitung der PGI-Daten mittels Cluster-Algorithmus 5.3.2 Definition von spot- oder clusterbasierten Klassifikationsmodellen 5.4 Ergebnisse der PGI-Detektionsfähigkeit 5.4.1 Auswertung für Patienten mit Prostata-Tumor 5.4.2 Auswertung für Patienten mit Tumoren im Kopf-Hals-Bereich 5.5 Diskussion 6 Genauigkeit zweier Reichweiteverifikationsmethoden – bizentrischer Vergleich 6.1 Material und Methoden 6.1.1 Bildgebung 6.1.2 Bestrahlungsplanung 6.1.3 Durchführung und Auswertung 6.2 Ergebnisse 6.3 Diskussion 7 Zusammenfassung 8 Summary

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