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.

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