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Abstract

Radiation therapy is a cornerstone of cancer treatment, though its effectiveness is limited when treating radio-resistant, hypoxic, and motion-affected tumors, including pancreatic ductal adenocarcinoma (PDAC). To overcome these obstacles, heavy-ion irradiation emerges as a promising alternative to conventional radiotherapy for treating hypoxic and radio-resistant cases due to its favorable physical and biological properties. Simultaneously, delivering radiation over a short time frame, at so-called ultra-high dose rates (UHDR), offers the potential to mitigate intra-fractional motion and to enhance the therapeutic ratio by sparing healthy tissue. Combining these two advanced modalities to heavy-ion UHDR irradiation may therefore be of particular benefit when treating these challenging tumor instances. The objective of this work was to establish the technical basis for exploring heavy-ion UHDR irradiation and to determine its clinical potential. Firstly, the technical feasibility and dosimetric prerequisites were systematically assessed. Diamond detectors were characterized under densely ionizing carbon and oxygen ion irradiation at UHDR. The results confirmed their suitability for dosimetry in heavy-ion UHDR beams. Subsequent mechanistic studies were conducted to examine the radiochemical processes after various particle beam deliveries, followed by the first preclinical experiments with oxygen-ion UHDR to evaluate the biological response in PDAC models. Herein, this radiation quality proved iso-effective in vitro cell killing and in vivo tumor growth delay compared to conventional dose rates. Survival benefits of oxygen-ion UHDR have been demonstrated and support future investigations of this modality. Collectively, these results provide methodological and physical groundwork as well as the first biological evidence endorsing the clinical exploration of heavy-ion UHDR irradiation, particularly for tumors with limited therapeutic options.