Radiotherapy in a FLASH : Towards clinical translation of ultra-high dose rate electron therapy

Sammanfattning: FLASH radiotherapy (FLASH-RT) is a promising new approach to radiotherapy that has the potential to transform the field. By administering radiation at ultra-high dose rates (UHDR) on a millisecond timescale, FLASH-RT may increase normal tissue tolerance compared to conventional radiotherapy while maintaining the anti-tumoral effect. However, the short treatment times present unique physical and technical challenges that must be resolved to ensure safe clinical implementation. The overall aim of this thesis was to address some of these challenges and promote the clinical translation of electron FLASH-RT. Specifically, the studies included in this thesis aimed to develop, establish, and evaluate tools and procedures to measure, plan, and deliver the UHDR electron beam of a modified clinical linear accelerator.In conventional radiotherapy, transmission chambers are used for beam monitoring during treatment delivery. In the first part of this thesis, we showed that the charge collection efficiency of the accelerator’s built-in transmission chamber decreases substantially as the dose-per-pulse (DPP) increases. However, we also demonstrated that this issue could be overcome and that the operating range of the chamber could be extended up to the ultra-high DPP regime by adjusting its position, design, and operation. Our results suggest that a transmission chamber-based monitoring approach might also be employed in UHDR electron beams, which would make the procedure for FLASH-RT delivery similar to conventional delivery.In the second part of this thesis, we established and evaluated dosimetric procedures for preclinical and clinical UHDR irradiations. Accurate delivery of the desired dose is critical to enable robust radiobiological studies that can help identify the biological mechanisms underlying the sparing effect of FLASH-RT and provide guidance in selecting beam parameters to test in clinical studies. We also demonstrated the feasibility of FLASH-RT in a clinical setting by initiating treatments of veterinary patients and conducting a dose-escalation trial in canine patients with spontaneously developed tumours. Finally, we also investigated a passive intensity-modulation technique with the aim of reducing the risk of radiation-induced side effects resulting from heterogeneous dose distributions in upcoming clinical trials. Our findings indicate that this technique, which is compatible with FLASH-RT delivery, can enhance the homogeneity of the dose distribution compared to utilizing an open electron beam. In the work included in this thesis, we established and evaluated tools and procedures to enable accurate UHDR delivery in a preclinical and clinical setting, which is crucial for a safe path towards clinical translation of FLASH-RT.