ESTRO 2024 - Abstract Book

S5250 ESTRO 2024 1 University of Oxford, Department of Oncology, Oxford, United Kingdom. 2 University of Oxford, Department of Engineering Science, Oxford, United Kingdom. 3 University of Oxford, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford, United Kingdom Radiobiology - Normal tissue radiobiology

Purpose/Objective:

Radiotherapy is a standard treatment for brain cancers but not curative for aggressive tumours. Concurrent chemoradiotherapy, though effective in many solid tumours, is less prominent in brain cancer management due to poor penetration of many radiosensitisers through the blood-brain barrier (BBB) and enhancement of radiation toxicity by chemotherapeutics. Therapeutic ultrasound (US) has been shown to transiently open the BBB and safely improve drug delivery to the brain. Radiation delivered at ultra-high dose rate (FLASH radiation) has also been shown to reduce neuroinflammation compared to conventional dose rate radiation. This study sought to understand the safety and feasibility of combining both treatment modalities to achieve carboplatin-based chemoradiation therapy in a murine model.

Material/Methods:

B6 mice (age 4-6 weeks, both sexes) were subjected to an US protocol intended to induce BBB opening (500 kHz, 0.46 MPa, 10% duty cycle, 2-minute exposure), using a single bolus coadministration of microbubbles (MB) (~1*108/mouse) and carboplatin (carbo, 50 mg/kg). Some mice were sacrificed 1.5 hours after US treatment to study the pharmacokinetics of the carboplatin. Twenty-four hours after US treatment, the right hemisphere of the mice was irradiated at 20 Gy using a 6 MeV electron beam at both FLASH (FLASH IR, 2,000 Gy/s) and conventional (CONV IR, 0.1 Gy/s) dose rates. Mice were weighed regularly to assess the overall toxicity of the treatment. The integrity of the blood-brain barrier was analysed by dynamic contrast-enhanced MRI at various time points post radiotherapy. Neuroinflammation and neurotoxicity were studied by multiplexed imaging.

Results:

We found that US exposure can improve the carboplatin delivery to the brain but did not trigger significant acute neurotoxicity. In addition, US exposure reduced carboplatin's systemic toxicity in combination with conventional and FLASH radiotherapy, as shown by the averaged weight loss after treatment (Figure). Disruption of BBB by the US was restored one-week post-treatment. In both US-treated and non-US-treated groups, carboplatin with FLASH IR showed less neurotoxicity and neuroinflammation than Conv IR.

Conclusion: