Neuroprotection of Radiosensitive Juvenile Mice by Ultra-High Dose Rate FLASH Irradiation

Abstract

Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients’ quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective “FLASH effect” was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin+) and mature (NeuN+) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors.

FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy

“…Recent data investigating the neurocognitive development of juvenile (3-week old) mice showed a radioprotective FLASH effect following 8 Gy whole brain irradiation with ultra-high FLASH dose rates (4.4 × 10 6 Gy/s, 6 MeV electrons) when compared to conventional dose rates (0.077 Gy/s, 6 MeV electrons) [22]. Mice were subjected to several neurocognitive tests following irradiation and in all cases the performance of the FLASH-irradiated animals was indistinguishable from the control group, whereas conventional irradiation caused a significant detriment.…”

“…It was suggested that the neurocognitive benefits of FLASH irradiation was due to a preservation of the neurogenic niche and neurogenesis in the FLASH treated mice, with conventional dose-rate-irradiated mice showing considerably lower levels of immature and mature neurons four months post-irradiation. Furthermore, the long-term benefits of FLASH on pituitary function was also investigated and it was found that 8 Gy conventional dose-rate-irradiated mice had a two-fold reduction in levels of plasma growth hormone levels one-week post-treatment compared to the non-irradiated controls, whereas no significant decrease was observed in the FLASH-irradiated animals [22]. Aside from mice, the FLASH effect has also been confirmed in mini-pigs and cats, higher animal models that are more similar to humans [14].…”

Translational Research in FLASH Radiotherapy—From Radiobiological Mechanisms to In Vivo Results

“…A recent study by Alaghband et al [ 49 ] investigated the potential for FLASH therapy to preserve the function compared to conventional radiotherapy for the whole brain irradiation of juvenile mice. A whole brain dose of 8 Gy was delivered at a dose rate of 0.077 Gy/s for conventional radiotherapy and 4.4 × 10 6 Gy/s for FLASH radiotherapy.…”

Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms

“…A first clinical application has been reported ( 6 ) and new clinical trials are being approved. Furthermore the potential use of FLASH in pediatrics (e.g., in medulloblastoma) has been cited from studies in juvenile mice ( 27 ).…”