Cancer therapy with high-energy particles has proved to be beneficial over the last 10 years. Protons are regarded as being more advantageous because of their distinctive physical depth dose distribution that allows dose conformation to the tumor while sparing normal tissue. In this study, the relative biological effectiveness (RBE) values for the 200-MeV clinical proton beam at iThemba LABS were measured at strategic positions along a 5 cm Spread-Out-Bragg-Peak (SOBP). RBE values were evaluated at the initial plateau of the virgin beam (24.2 mm in Perspex), and at the middle part, distal part and distal edge (12.4% max. dose) along the SOBP (depth in Perspex= 161.4, 181.3 and 207.7 mm respectively). Biological systems used were Chinese hamster ovary cells (CHO-Kl) for both cell survival and micronuclei frequencies as well as human T-lymphocytes for micronuclei frequency analysis. (60)^Co y-irradiation served as a reference. Cell survival measurements yielded RBE values of 1.17 at the distal part and 1.62 at the distal edge (12.4 max. dose). For micronuclei analysis, a limiting RBEap+ay value of 1.3 at the distal part was observed. Using T-lymphocytes, RBEap+/ay values calculated were 2.1, 2.7 and 3.2 at the middle part, distal part and distal edge, respectively. These results show an increase in RBE with depth of penetration and are explained by an increase in ionization density at the end of the SOBP. This is influenced by a high fraction of low-energy protons at that position. Protons were found to be most potent per unit dose towards the end as they slow down to a complete stop. It is recommended that an RBE value slightly greater than the current 1.1 be applied in therapy. Also, that the less steep biological effective depth dose curve be taken into account when dose planning. / Thesis (MSc. ARST) North-West University, Mafikeng Campus, 2003

No description available.

Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: The assignment of radiation weighting factors to high energy neutron sources is important as there is reason to believe that neutron relative biological effectiveness (RBE) may be related to the inherent radiosensitivity of different individuals. A study was undertaken to quantify the inherent radiosensitivities of lymphocytes obtained from different donors to 60Co y-rays and p(66)/Be neutrons. For this a novel semi-automated image analysis process has been employed. In addition the responses of lymphocytes with different inherent radiosensitivities have also been tested using Auger electrons emitted by 123I. Methods: The RBE of neutrons was determined from dose-response curves for lymphocytes from different donors. Isolated T-lymphocytes irradiated in vitro were cultured to induce micronuclei in binucleated cells and micronuclei (MN) formations numerated using a semi-automated Metafer microscope system. The accuracy in obtaining dose response curves with this method has been tested by evaluating dispersion parameters of MN formations in the response to the different treatment modalities. Differences in the inherent radiosensitivities of cells from different donors were ascertained using 95 % confidence ellipses. [123I]Iododeoxyuridine was prepared in a formulation that allows incorporation of 123I into the DNA of lymphocytes. Micronucleus formations to this treatment were evaluated in lymphocytes with established differences in inherent radiosensitivities. Results: The image analysis system proved to be consistent in detecting micronuclei frequencies in binucleated lymphocytes. As a result, differences in the inherent radiosensitivities of different individuals were distinctive and could be stated at the 95% confidence level. The inter-individual radiosensitivity variations were considerably smaller for blood cells exposed to high energy neutrons compared to 60Co y-rays. Relative biological effectiveness (RBEM) values between 2 and 13 were determined that are highly correlated with the inherent radioresistance of lymphocytes obtained from different individuals. As such radiation weighting factors for high energy neutrons cannot be based on cytogenetic damage determined in lymphocytes from a single donor. Dispersion parameters for micronuclei formations proved to vary according to ionization density. The variation in RBE with neutron dose changed according to theoretical considerations and automated image analysis detection of MN is thus a suitable method to quantify radiation weighting factors. A clear reduction in the variation in radiosensitivity is noted for lymphocytes exposed to Auger electrons compared to 60Co y-rays. The effectiveness of Auger electrons from [123I]IUdR to induce biological damage is demonstrated as the number of disintegrations needed to yield micronuclei formations was found to be more than two orders of magnitude less than that of other compounds. An increase in the RBE of Auger electrons with radioresistance can be inferred from these findings and constitutes a basis for therapeutic gain in treating cells compared to using radioisotopes emitting low-LET radiation. / AFRIKAANSE OPSOMMING: Agtergrond: Die bepaling van straling gewigsfaktore vir hoë energie neutron bronne is belangrik, aangesien daar rede is om te glo dat die relatiewe biologiese effektiwiteit (RBE) kan verband hou met die inherente stralings sensitiwiteit van verskillende individue. Hierdie studie is onderneem om die inherente radiosensitiwiteit van limfosiete verkry vanaf verskillende skenkers te kwantifiseer na blootstelling aan 60Co y -strale en p(66)/Be neutrone. Vir hierdie doel is daar van 'n semi-outomatiese beeldontleding metode gebruik gemaak. Daarbenewens is die reaksie van limfosiete met vooraf bepaalde inherente radiosensitiwiteite ook getoets aan die hand van Auger elektrone wat uitgestraal word deur 123I. Metodiek: Die RBE van neutrone was bepaal uit dosis mikrokerne frekwensie verwantskappe verkry vir limfosiete. Geïsoleerde T-limfosiete was in vitro bestraal en gekweek om mikrokerne te vorm in dubbelkernige selle. Die mikrokerne was gekwantifiseer deur die gebruik van 'n semi-outomatiese Metafer mikroskoop stelsel. Die akkuraatheid in die verkryging van dosis-effek krommes met hierdie metode is getoets deur die ontleding van verspreidings parameters van MN vorming in reaksie op behandeling met die verskillende stralings modaliteite. Verskille in die inherente stralingsensitiwiteite van die selle van verskillende skenkers was vasgestel deur die konstruksie van 95 % betroubaarheidsinterval ellipse. [123I]Iododeoxyuridine was ook berei om 123I in die DNA van limfosiete in te bou. Die mikrokerne vorming op die behandeling is beoordeel in limfosiete met gevestigde verskille in inherent radiosensitiwiteite. Resultate: Die beeld analise stelsel bewys om konsekwent te wees in die opsporing van mikrokerne wat vorm in dubbelkernige limfosiete. Verskille in die inherente radiosensitiwiteite van verskillende skenkers kon vasgestel word op die 95 % betroubaarheidsvlak. Die skommeling in inter-individuele stralings sensitiwiteite was kleiner vir bloed selle blootgestel aan hoë-energie neutrone in vergelyking met 60Co y-strale. Relatiewe biologiese effektiwiteit (RBEM) waardes tussen 2 en 13 is bepaal wat sterk verband hou met die inherente radioweerstandbiedendheid van limfosiete verkry vanaf verskillende persone. As sodanig kan straling gewigsfaktore vir hoë energie neutrone nie gebaseer word op sitogenetiese skade in limfosiete van 'n enkele skenker nie. Verspreidings parameters vir mikrokern vorming het gewissel as ‘n funksie van ionisasiedigtheid van die straling. Die verandering in RBE met neutron dosis verloop volgens teoretiese oorwegings en die semi-outomatiese beeldontledings metode om mikrokerne op te spoor is dus geskik om stralings gewigsfaktore te kwantifiseer. 'n Duidelike afname in die verandering in die stralingsensitiwiteite is waargeneem vir limfosiete blootgestel aan Auger elektrone in vergelyking met 60Co y-strale. Die hoë doeltreffendheid van Auger elektrone afkomstig van [123I]IUdR om biologiese skade te veroorsaak, word weerspieël deur die feit dat die getal disintegrasies wat nodig is om mikrokerne te vorm meer as twee ordes grootte minder is as dié van ander verbindings. 'n Toename in die RBE van Auger elektrone in selle wat radioweerstandbiedend is kan afgelei word uit hierdie bevindinge. Dit vorm 'n basis vir terapeutiese wins in die behandeling van selle in vergelyking met die gebruik van radio-isotope wat lae ionisasie digthede tot stand bring.

L’hadronthérapie par ions carbone représente une modalité de radiothérapie alternative très attractive du fait des propriétés physiques et biologiques de ce type de particules. Les chondrosarcomes, tumeurs radio-résistantes à différentiation cartilagineuse, sont en première ligne pour le traitement par ions carbone. Cependant, les effets secondaires sur les tissus sains environnants sont peu ou mal connus. Ce projet a pour but l’étude des effets directs des ions accélérés dans un modèle 3D de cartilage sain et pathologique proche de l’homéostasie humaine et le développement de nouveaux outils de calculs d’efficacité biologique relative (EBR). Dans un premier temps, nous nous sommes intéressés aux séquelles radio-induites sur le cartilage articulaire dans un contexte d’hadronthérapie par ions carbone. En culture 2D physioxique (2% d’O2), l’efficacité biologique relative des ions carbone (transfert d’énergie linéique ou TEL intermédiaire) comparée aux rayons X a été évaluée à 2,6. Ceci a été corrélé à une plus forte induction de sénescence radio-induite. Cependant, cet effet différentiel n’a pas été retrouvé en utilisant un modèle 3D de cartilage articulaire. L’efficacité biologique relative des ions accélérés semble donc surévaluée, en utilisant des cultures en monocouche, par rapport à la 3D. Dans un deuxième temps, un modèle 3D de chondrosarcome a été développé pour des études d’hadronbiologie. Après plusieurs obstacles techniques, des méthodes d’extraction protéique et d’immunohistochimie ont été mises au point. Une nouvelle méthode d’évaluation de l’EBR en 3D basée sur la cinétique d’induction de la protéine γ-H2AX a été proposée. / Hadrontherapy using carbon ions has many advantages due to physical and biological properties of this type of particle. Chondrosarcoma, a cartilaginous radio-resistant tumor, has been successfully treated using carbon ions. However, potential side effects to the surrounding healthy tissues are still poorly known. This project aims to study the direct effects of carbon ions in a 3D model of healthy articular cartilage and chondrosarcoma close to human homeostasis, in order to provide new tools for the evaluation of the relative biological effectiveness (RBE).The first part of the project was dedicated to the evaluation of carbon ions-induced impact on articular cartilage in the context of chondrosarcoma treatment. Compared to X-rays, the relative biological effectiveness of intermediate-LET carbon ions scored 2.6 in 2D monolayer culture. This was correlated with a stronger induction of cellular senescence. However, this differential effect was not reproduced using a 3D model of articular cartilage. Thus, the relative biological effectiveness of accelerated ions is probably overestimated using monolayer cultures (2D), compared to 3D. In the second part of this work, we developed a 3D chondrosarcoma model for hadronbiology studies. Protein extraction and immunohistochemistry protocols were developed. A new RBE evaluation method based on γ -H2AX repair kinetic in 3D, was proposed.

The ICRP recommends a radiation weighting factor of one for all low-LET radiation. However, many experimental studies find inconsistencies between low-LET RBE and the ICRP's current radiation weighting factor. Generally, there is evidence that dependence exists between radiation energy and radiation RBE where lower energy radiations tend to have a greater biological effect than higher energy radiation. Specifically, the radiations of tritium and carbon K-shell x-rays have been studied in numerous experiments and the biological effects of both of these radiations are consistently greater than that of Co-60. In this work, the relationship between radiation energy and radiation effect has been investigated with the use of a newly developed double strand break (DSB) yield estimation algorithm. This algorithm makes use of a detailed solenoidal 30 nm DNA chromatin model to describe the radiation-sensitive biological target. In addition to the DNA model, NOREC, an event by event Monte Carlo code, was used in this algorithm to characterize the electron track. As an alternative to the conventional approach of computationally simulating DNA damage by spatial overlay of an electron track on DNA, this algorithm instead focuses on quantifying the distance between ionizations in an electron track and next determining the likelihood that any given ionization pair forms a DSB. The first step of the algorithm involves electron characterization while the second step relies on DNA molecule characterization. By assuming a DSB biological endpoint and determining the DSB yield as a function of electron energy, energy dependent RBE values were estimated for monoenergetic electrons from 10 eV to 1 MeV. Photon RBE values, x-ray RBE values and radionuclide RBE values were also calculated and reported in this work in addition to electron RBE values. Photon RBE values were estimated based upon the electron RBE calculation. Photon RBE values were reported from 1 eV to 10 MeV. In turn, x-ray RBE values were calculated based upon photon values for several tube voltage and filter combinations. Finally, RBE values for over 1000 radionuclides were estimated and reported.

Derzeit gibt es eine intensive Debatte über die Notwendigkeit, Variationen der relativen biologischen Wirksamkeit (RBE) in der Protonentherapie zu berücksichtigen. Hier wurde die Variabilität der RBE für späte strahleninduzierte Hirnverletzungen (RIBI) untersucht, die nach einer Protonentherapie von Gliom-Hirntumorpatienten diagnostiziert wurden. Eine Gliomkohorte wurde definiert und auf späte RIBI untersucht, die in der Patienten-Nachsorge beobachtet wurden. Die RIBI Läsionen wurden mit linearen Energietransfer- und variablen RBE-Verteilungen korreliert, die unter Verwendung eines etablierten Monte-Carlo Frameworks berechnet wurden. Ein klinisches RBE Modell wurde erstellt und zur Evaluierung neuartiger Behandlungsstrategien angewendet. Die periventrikuläre Region wurde als anatomischer Risikofaktor für RIBI identifiziert und als neues Risikoorgan in die Protonenbehandlungsplanung an der Universitäts Protonen Therapie Dresden aufgenommen. Die Arbeit demonstriert die klinische Relevanz und präsentiert erste translatorische Schritte hin zur biologisch optimierten Protonentherapie unter Verwendung einer variablen RBE. / Currently, there is an intense debate on the need to consider variations in relative biological effectiveness (RBE) in proton therapy. Here, the variability of RBE was investigated for late radiation-induced brain injuries (RIBI) observed after proton therapy in glioma brain tumor patients. A glioma cohort was defined and evaluated for late RIBI observed in patient follow-up. Injury lesions were correlated to linear energy transfer and variable RBE distributions simulated using an established Monte-Carlo framework. A clinical RBE model was established and applied in treatment response assessment of novel treatment strategies. The periventricular region was identified as an anatomical risk factor for RIBI and incorporated as a new organ at risk in proton treatment planning at University Proton Therapy Dresden. The thesis demonstrates the clinical relevance and presents first translational steps towards biologically optimized proton therapy using a variable RBE.

L'Efficacité Biologique Relative (EBR) des faisceaux de protons énergétiques (70-250 MeV) utilisés dans les différents centres de protonthérapie est classiquement estimée à 1,10 par rapport aux photons du Cobalt-60. Bien qu'en accord avec la mesure de la régénération des cryptes intestinales chez la souris après exposition à une dose unique de 10 à 15 Gy, cette valeur moyenne a été contestée par la microdosimétrie. Ces incertitudes nous ont conduits à analyser l'effet des protons mis en œuvre dans les deux faisceaux médicaux (76 et 201 MeV) du Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO) sur deux lignées cellulaires humaines tumorales, et en partie sur une lignée fibroblastique. Les résultats font apparaître une différence de la valeur de l'EBR pour la survie au rayonnement dans la partie distale du SOBP (Spread-Out Bragg Peak) en fonction de l'énergie incidente, ainsi qu'une absence de corrélation entre la réponse en survie et l'incidence des cassures double-brin de l'ADN dans le faisceau de 76 MeV. Nous montrons cependant, grâce à l'utilisation de lignées défectives dans les voies de signalisation et de réparation des cassures double-brin de l'ADN par le D-NHEJ, que ces voies déterminent la valeur de l'EBR dans la partie distale du SOBP de 76 MeV. La réponse aux dommages de l'ADN dans cette région suggère que les dommages létaux appartiennent à la classe des “lésions complexes” (LMDS) de l'ADN. D'autre part, il apparaît que la fluence des particules constitue un paramètre majeur qui doit être pris en compte dans la partie distale des faisceaux. / Treatment planning in proton therapy uses a generic value for the Relative Biological Efficiency (RBE) of 1.1 relative to 60Co gamma-rays throughout the Spread Out Bragg Peak (SOBP). We have studied the variation of the RBE at three positions in the SOBP of the 76 and 201 MeV proton beams used for cancer treatment at the Institut Curie Proton Therapy in Orsay (ICPO) in two human tumor cell lines using clonogenic cell death and the incidence of DNA double-strand breaks (DSB) as measured by pulse-field gel electrophoresis without and with endonuclease treatment to reveal clustered lesions as endpoints.The RBE for induced cell killing by the 76 MeV beam increased with depth in the SOBP. However for the 201 MeV protons it was close to that for 137Cs gamma-rays and did not vary significantly. The incidence of DSBs and clustered lesions was higher for protons than for 137Cs g-rays, but did not depend on the proton energy or the position in the SOBP.In the second part of our work, we have shown using cell clones made deficient for known repair genes by stable or transient shRNA transfection, that the D-NHEJ pathway determine the response to protons. The response of DNA damages created in the distal part of the 76 MeV SOBP suggests that those damages belong to the class of DNA "complex lesions" (LMDS). It also appears that the particle fluence is a major determinant of the outcome of treatment in the distal part of the SOBP.

L'interaction des rayonnements ionisants avec le vivant est marquée par des phénomènes stochastiques importants aussi bien en termes de dosimétrie physique que des effets biologiques induits. Cette thèse aborde trois problématiques de la thérapie et de l'estimation du risque des radiations pour la santé, à l'aide d'outils de modélisation et de simulations Monte Carlo. En effet, des calculs de l'énergie spécifique dans des volumes de différentes tailles ont montré que les amplitudes des fluctuations dépendent fortement de la taille de la cible. Elles sont particulièrement grandes dans le cas des cibles nanométriques. À partir de ces calculs, une étude sur la taille des dosimètres implantables pour le monitorage des traitements de radiothérapie a montré que des dimensions au moins micrométriques sont nécessaires pour assurer des mesures fiables. Les mêmes calculs ont permis l'analyse des effets de faibles doses d'irradiation, notamment la compatibilité de différentes tailles de cibles avec des données expérimentales d'aberrations chromosomiques. Les résultats suggèrent que l'activation du réseau mitochondrial peut être liée au déclenchement de mécanismes de radiorésistance dans les cellules CAL51. Finalement, un nouveau modèle (NanOx) de prédiction de l'efficacité de l'hadronthérapie (radiothérapie par faisceaux d'ions) est présenté et appliqué à la lignée cellulaire V79. Ce modèle est complètement stochastique et intègre les calculs de dosimétrie à plusieurs échelles pour modéliser des effets locaux et non locaux pouvant correspondre respectivement à des lésions de l'ADN et à un stress oxydatif / The interaction between ionizing radiation and living tissues is characterized by stochastic phenomena with non-negligible consequences both in terms of physical dosimetry and induced biological effects. The present work addresses three issues concerning radiotherapy and the estimation of radiation risks for health, by means of modeling tools and Monte Carlo simulations. Indeed, specific energy calculations in volumes of different sizes showed that the level of fluctuations strongly depends on the target size. Such fluctuations are especially high in the case of nanometric targets. Based on these calculations, a study about the size of implantable dosimeters employed in the monitoring of radiotherapy treatments demonstrated that these dosimeters should have at least micrometric dimensions in order to ensure reliable measurements. The same calculations have allowed the analysis of the effects of low doses of radiation, namely the compatibility between different target sizes and experimental data regarding chromosomal aberrations. The results suggest that the activation of the mitochondrial network may be linked to the triggering of radioresistance mechanisms for the CAL51 cell line. Finally, a new model (NanOx) to predict the effectiveness of particle therapy (radiotherapy with ion beams) is presented and applied to the V79 cell line. Such a model is completely stochastic and integrates the dosimetry calculations at multiple scales for modeling local and non-local effects, which can correspond respectively to DNA lesions and cellular oxidative stress

Protonen töten Zellen wirksamer ab als Photonen. Die klinisch verwendete konstante relative biologische Wirksamkeit (RBW) für Protonen vernachlässigt jedoch erste klinische Evidenz einer RBW-Variabilität, die vom linearen Energietransfer (LET) abhängt. Diese Arbeit trägt dazu bei, die RBW-Variabilität in Protonen-Bestrahlungsplänen zu berücksichtigen, um potenzielle Nebenwirkungen zu vermindern. Zuerst wurde ein erhöhtes Risiko für RBW-induzierte Nebenwirkungen bei Hirntumorpatienten festgestellt. Dies konnte jedoch nicht systematisch durch klinische Planungsstrategien reduziert werden. Zweitens ergab eine multizentrische europäische Studie, dass die zentrums-spezifischen, nicht standardisierten LET-Berechnungen erheblich voneinander abweichen. Eine harmonisierte LET-Definition wurde vorgeschlagen und reduzierte die Variabilität zwischen den Zentren auf ein klinisch akzeptables Niveau, was künftig eine einheitliche Dokumentation des Therapieergebnisses ermöglicht. Abschließend wurden vier Strategien zur RBW-Reduktion in der Planoptimierung bei Hirntumorpatienten angewandt, die das Risiko für Nekrose und Erblindung erheblich reduzierten. LET-Optimierung in Hochdosisregionen erscheint besonders geeignet, um die Sicherheit der Patientenbehandlung künftig weiter zu verbessern.:List of Figures vii List of Tables viii List of Acronyms and Abbreviations ix 1 Introduction 1 2 Theoretical background 3 2.1 Proton interactions with matter 4 2.2 Biological effect of radiation 8 2.2.1 Linear-quadratic model 8 2.2.2 Relative biological effectiveness 9 2.3 Proton beam delivery and field formation 13 2.4 Treatment planning 14 2.4.1 Patient modelling and structure definition 15 2.4.2 Treatment plan optimisation 16 2.4.3 Treatment plan evaluation 19 2.5 Proton therapy uncertainties and mitigation strategies 22 2.5.1 Clinical mitigation strategies 23 2.5.2 Optimisation approaches beyond absorbed dose 26 3 Variable biological effectiveness in PBS treatment plans 29 3.1 LET and RBE recalculations of proton treatment plans with RayStation 30 3.1.1 Monte Carlo dose engine 30 3.1.2 Monte Carlo scoring extensions 32 3.1.3 Graphical user interface 33 3.2 LET assessment and the role of range uncertainties 36 3.2.1 Patient cohort and treatment plan creation 37 3.2.2 Simulation of range deviations 38 3.2.3 Treatment plan recalculation settings 39 3.2.4 Resulting impact of range deviations 40 3.3 Patient recalculations in case of side effects 46 3.3.1 Image registration and range prediction 48 3.3.2 Retrospective treatment plan assessment 49 3.4 Benefit of an additional treatment field 50 3.4.1 Patient and treatment plan information 50 3.4.2 Results of variable RBE recalculations 51 3.5 Discussion 51 3.6 Summary 59 4 Status of LET and RBE calculations in European proton therapy 61 4.1 Study design 62 4.1.1 Treatment planning information 64 4.1.2 Data processing and treatment plan evaluation 67 4.2 Treatment plan comparisons in the water phantom 68 4.2.1 Absorbed dose evaluation 69 4.2.2 Centre-specific LET calculations 69 4.2.3 Harmonised LET calculations 71 4.3 Treatment plan comparisons in patient cases 72 4.3.1 Dose-averaged linear energy transfer for protons 73 4.3.2 Centre-specific RBE models and parameters 76 4.4 Discussion 77 4.5 Summary 82 5 Biological treatment plan optimisation 83 5.1 Treatment plan design 84 5.1.1 Clinical goals 86 5.1.2 Novel treatment plan optimisation approaches 87 5.2 Treatment plan quality assessment with a constant RBE 90 5.3 Assessment of NTCP reductions with a variable RBE 90 5.4 Discussion 95 5.5 Conclusion 100 6 Summary 103 7 Zusammenfassung 107 Bibliography 111 Danksagung 137 / Protons are more effective in cell killing than photons. However, the clinically applied constant proton relative biological effectiveness (RBE) neglects emerging clinical evidence for RBE variability driven by the linear energy transfer (LET). This thesis aims to safely account for RBE variability in proton treatment plans to mitigate potential side effects. First, an elevated risk for RBE induced overdosage was found in brain tumour patients. However, this could not be mitigated systematically by clinical planning strategies. Second, a multicentric European study revealed that centre-specific non-standardised LET calculations differed substantially. A harmonised LET definition was proposed which reduced the inter-centre variability to a clinically acceptable level and allows for future consistent outcome reporting. Finally, four strategies to include RBE variability in treatment plan optimisation were applied to brain tumour patients, which considerably reduced the estimated risk for necrosis and blindness. Of these, LET optimisation in high dose regions may be suited for clinical practice to further enhance patient safety in view of a variable RBE.:List of Figures vii List of Tables viii List of Acronyms and Abbreviations ix 1 Introduction 1 2 Theoretical background 3 2.1 Proton interactions with matter 4 2.2 Biological effect of radiation 8 2.2.1 Linear-quadratic model 8 2.2.2 Relative biological effectiveness 9 2.3 Proton beam delivery and field formation 13 2.4 Treatment planning 14 2.4.1 Patient modelling and structure definition 15 2.4.2 Treatment plan optimisation 16 2.4.3 Treatment plan evaluation 19 2.5 Proton therapy uncertainties and mitigation strategies 22 2.5.1 Clinical mitigation strategies 23 2.5.2 Optimisation approaches beyond absorbed dose 26 3 Variable biological effectiveness in PBS treatment plans 29 3.1 LET and RBE recalculations of proton treatment plans with RayStation 30 3.1.1 Monte Carlo dose engine 30 3.1.2 Monte Carlo scoring extensions 32 3.1.3 Graphical user interface 33 3.2 LET assessment and the role of range uncertainties 36 3.2.1 Patient cohort and treatment plan creation 37 3.2.2 Simulation of range deviations 38 3.2.3 Treatment plan recalculation settings 39 3.2.4 Resulting impact of range deviations 40 3.3 Patient recalculations in case of side effects 46 3.3.1 Image registration and range prediction 48 3.3.2 Retrospective treatment plan assessment 49 3.4 Benefit of an additional treatment field 50 3.4.1 Patient and treatment plan information 50 3.4.2 Results of variable RBE recalculations 51 3.5 Discussion 51 3.6 Summary 59 4 Status of LET and RBE calculations in European proton therapy 61 4.1 Study design 62 4.1.1 Treatment planning information 64 4.1.2 Data processing and treatment plan evaluation 67 4.2 Treatment plan comparisons in the water phantom 68 4.2.1 Absorbed dose evaluation 69 4.2.2 Centre-specific LET calculations 69 4.2.3 Harmonised LET calculations 71 4.3 Treatment plan comparisons in patient cases 72 4.3.1 Dose-averaged linear energy transfer for protons 73 4.3.2 Centre-specific RBE models and parameters 76 4.4 Discussion 77 4.5 Summary 82 5 Biological treatment plan optimisation 83 5.1 Treatment plan design 84 5.1.1 Clinical goals 86 5.1.2 Novel treatment plan optimisation approaches 87 5.2 Treatment plan quality assessment with a constant RBE 90 5.3 Assessment of NTCP reductions with a variable RBE 90 5.4 Discussion 95 5.5 Conclusion 100 6 Summary 103 7 Zusammenfassung 107 Bibliography 111 Danksagung 137