ESTRO 2024 - Abstract Book

S5308 3174

Radiobiology - Normal tissue radiobiology

ESTRO 2024

Digital Poster

Effects of whole brain conventional or FLASH proton irradiation in Sprague Dawley rats

Charles V Vorhees 1,2 , Chiho Sugimoto 1 , Samantha L Regan 1 , Emily M Pitzer 1 , Adam L Fritz 1 , Brooke M Gollaway 1 , Mathieu Sertorio 3 , Anthony E Mascia 3 , Ralph E Vatner 3,4 , John P Parentesis 1,4 , Michael T Williams 1 1 Cincinnati Children's Hospital Medical Center, Neurology, Cincinnati, USA. 2 University of Cincinnati College of Medicine, Pediatrics, Cincinnati, USA. 3 University of Cincinnati College of Medicine, Radiation OncologyPediatrics, Cincinnati, USA. 4 Cincinnati Children's Hospital Medical Center, Oncology, Cincinnati, USA

Purpose/Objective:

Purpose/Objective: Brain radiation prolongs the life of cancer patients, but it can also impair neurocognitive function [1-4]. Cranial irradiation is an essential treatment for many brain tumors. Proton radiotherapy can decrease toxicity by reducing radiation exposure of healthy brain tissue, while delivering equivalent anti-tumor efficacy compared with X-ray radiotherapy [5, 6]. A study in children with medulloblastoma identified superior intellectual outcomes in patients treated with proton compared with photon radiotherapy [7]. However, while proton therapy reduces cognitive dysfunction, it does not remove it completely and there is need for further improvement in cognitive outcomes. One potential prospect for greater protection is to use ultra-high dose rates of proton radiation, known as FLASH. With electron irradiation, the FLASH effect was demonstrated in zebrafish, mice, minipigs, and cats [8-12]. The first experiment herein established the cognitive domains affected by rats exposed to head-directed proton irradiation at a conventional dose rate. This was followed by studies that examined the effects of FLASH compared with conventional proton dose rates in adult and young rats. Material/Methods: Sprague Dawley rats received single fraction whole brain proton irradiation. Experiment 1: adult male rats (10/group) received a single dose of 0, 11, 14, 17, or 20 Gy proton at a dose rate of 1 Gy/s. Rats were tested for 5 weeks post-irradiation for activity, coordination, and startle response. Starting at 6 weeks post irradiation, cognitive assessments were done for novel object recognition (NOR), egocentric learning in the Cincinnati water maze (CWM), and allocentric learning, reference memory, and proximal cue learning in the Morris water maze (MWM). Experiment 2: adult male rats were irradiated with protons at 18 Gy at a conventional dose rate of 1 Gy/s (Conv), FLASH at 60 Gy/s (FLASH-60) or 95 Gy/s (FLASH-95), or sham to Controls (n ³22/group). Rats were tested for 4 weeks post-irradiation in open-field, acoustic startle (ASR), and tactile startle (TSR) with or without prepulses, novelty preference, radial water maze (RWM), MWM acquisition and reversal, CWM-A , MWM shift and shift reversal, CWM-B , and NOR. Experiment 3: postnatal day 11 male and female rats were treated with 0, 5, or 8 Gy protons at 1 Gy/s or FLASH 100 Gy/s. Rats were tested as adults for open-field activity, ASR, TSR with or without prepulses, NOR, CWM-A, RWM, MWM, conditioned freezing, and CWM-B. Material/Methods:

Results:

Results: Experiment 1: Proton exposure had the largest effect at reducing activity and prepulse inhibition of startle 1-week post-irradiation; these effects gradually diminish across weeks. 6-weeks post-irradiation, there were no effects on NOR, however proton exposure impaired egocentric (CWM) and allocentric learning and caused reference memory deficits (MWM) but did not affect proximal cue learning or swimming ability. Proton groups had reduced striatal levels of the dopamine transporter, tyrosine hydroxylase, and the dopamine receptor D1, effects consistent with egocentric learning deficits. Experiment 2: There was a decrease in activity and increased