FLASH Effects Induced by kV X-Rays in a Murine Skin Model

Abstract

<h3>Purpose/Objective(s)</h3> Current research on FLASH dose rate radiotherapy is predominantly performed with advanced proton or electron accelerators of limited access to the laboratory researcher. Stationary anode orthovoltage x-ray irradiators would be desirable but are currently incapable of supporting the power requirements to operate at FLASH dose rates. In this study, we investigate the use of rotating anode x-ray tubes to overcome these limitations. We present the dosimetric characterization of a rotating anode x-ray system for laboratory FLASH research and its implementation for a pilot study of radiation skin toxicities in mice. <h3>Materials/Methods</h3> A high-capacity rotating anode x-ray tube was installed in our laboratory with a 75-kW generator, operating at 150 kVp with 0.025 mm Cu added filtration. Calibrated radiographic film was irradiated at varying depths in kV solid water to measure output, beam profiles, and depth-dose parameters (PDD). A variety of wild-type mice (GR/GRT, CMV) were irradiated to the hind flank to 38 or 48 Gy at the highest achievable dose rate (FLASH-IR). Conventional dose rate irradiations (CONV-IR) to the same doses were performed at 3 Gy/min using a 220 kVp x-ray irradiator. Visible skin toxicities were assessed weekly and quantified using a skin scoring scale for endpoints of hair loss, erythema, and ulceration (n= 7 per dose at each dose rate). At 8-weeks post irradiation, skin samples were harvested and stained with H&E to assess pathological changes from FLASH-IR or CONV-IR x-rays. <h3>Results</h3> Dose rates peaked at 101 Gy/s in the cathode side of the radiation field from anode heel effects. The total field size at 46 mm SSD was 20 × 20mm². A useable region of 10 × 20 mm² for FLASH studies was defined as the cathode-half of the field, with an average dose rate of 96.1 ± 2.8 Gy/s. The PDD within this region falls to 67% at 5mm depth in solid water and 51% at 10 mm. At 4 weeks post irradiation, CONV-IR mice saw hair loss and erythema in the entire irradiated region, while all FLASH-IR mice retained hair in-field with no change in skin condition. By 8 weeks post irradiation, skin effects in all FLASH-IR mice did not progress beyond hair loss in field, while all CONV-IR mice had progressed to more severe skin toxicities. Pathological assessments are ongoing. Early analysis shows higher frequency of ulceration, dermis hyperplasia, and fibrosis from CONV-IR than FLASH-IR. <h3>Conclusion</h3> This study presents the first observation of FLASH effects induced by a single pulse of kV x-rays in an animal skin toxicity model. FLASH dose rates requisite for preclinical research are achievable with kV x-rays using rotating anode technology. X-ray FLASH effects in skin occur at comparable doses to those published for FLASH electrons and protons. The use of a single x-ray pulse suggests that average dose rate is the necessary condition, in contrast to fine pulse structure, for the induction of FLASH effects.