FLASH Effects Induced by Orthovoltage X-Rays

Purpose : This work describes the first implementation and in vivo study of FLASH effects induced by kilovoltage (kV) x-ray from a rotating anode x-ray source. Methods and Materials : A high-capacity rotating-anode x-ray tube with an 80-kW generator was implemented for preclinical FLASH radiation research. A custom 3D printed immobilization and positioning tool was developed for reproducible irradiation of a mouse hind limb. Calibrated Gafchromic (EBT3) film and thermoluminescent dosimeters (LiF; Mg,Ti) were used for in-phantom and in vivo dosimetry. Healthy FVB/N and FVBN/C57BL/6 outbred mice were irradiated on one hind leg to doses up to 43 Gy at FLASH (87 Gy/s) and conventional (CONV; < 0.05 Gy/s) dose rates. The radiation doses were delivered using a single pulse with the widths up to 500 milli-seconds and 15 minutes at FLASH and CONV dose rates. Histological assessment of radiation-induced skin damage was performed at 8 weeks post-treatment. Tumor growth suppression was assessed using a B16F10 flank tumor model in C57BL6J mice irradiated to 35 Gy at both FLASH and CONV dose rates. Results : FLASH-irradiated mice experienced milder radiation-induced skin injuries than CONV-irradiated mice, visible by 4 weeks post-treatment. At 8 weeks post-treatment, normal tissue injury was significantly reduced in FLASH-irradiated animals compared to CONV-irradiated animals for histological endpoints including inflammation, ulceration, hyperplasia and fibrosis. No difference in tumor growth response was observed between FLASH and CONV irradiations at 35 Gy. The normal tissue sparing effects of FLASH irradiations were only observed for high-severity endpoint of ulceration at 43 Gy, which suggests the dependency of biological endpoints to FLASH radiation dose. Conclusion : Rotating anode x-ray sources can achieve FLASH dose rates in a single pulse with dosimetric properties suitable for small animal experiments. We observed FLASH normal tissue sparing of radiation toxicities in mouse skin irradiated at 35 Gy with no sacrifice to tumor growth suppression. This study highlights an accessible new modality for laboratory study of the FLASH effect.