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Abstract
Abstract Patients who undergo radiation therapy (RT), particularly fractionated courses, often develop lymphopenia. Clinical outcome for various cancer types, including brain tumors, identifies lymphopenia as a negative prognostic factor. The mechanism for RT induced lymphopenia is unclear. Simulated models suggest the volume of blood flowing through a radiation field could play a crucial role in death of radiosensitive lymphocytes. FLASH RT is ultrahigh dose rate administration of RT, >100 times faster dose rate than standard RT that has been observed to improve the therapeutic ratio in preclinical models by preferential normal tissue sparing. Hypothesized mechanisms include chemical reactions depleting oxygen in well oxygenated normal cells creating radioresistance, differing pro-inflammatory signaling impacting tumor and normal tissue, and less impact on circulating immune cells consequent to decreased proportion exposed during a treatment session which may enhance antineoplastic response. We designed the novel FLASH kV x-ray cabinet system for preclinical laboratory research (FLASH-SARRP) to deliver ultra-high dose rates up to 100 Gy/s as well as conventional dose rates of 1.0 Gy/s to facilitate comparative studies. A custom designed docking system was developed to reproducibly position and immobilize mouse for stereotactic radiation of the brain. Dose and dose rate measurements were performed with calibrated Gafchromic EBT3 film in solid water with 0.025 mm additional copper filter. FLASH-SARRP system delivered kV x-rays at an average dose-rate of 79.2±2.1Gy/s corresponding to 10 mm depth in the immobilized mouse brain. For the delivery of 15 Gy, treatment duration was 0.2 seconds for FLASH RT administration whereas it was 244 seconds for conventional dose rate. We successfully designed a high-precision platform to study partial brain x-ray FLASH effects in mice and studies are ongoing to assess differential impact on normal brain tissue, circulating cytokines, and immune cell populations for single dose and fractionated administration of FLASH and standard radiotherapy.
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