Review of Conventional and High Dose Rate Brain Radiation (FLASH): Neurobehavioural, Neurocognitive and Assessment Issues in Rodent Models

Abstract

Ionising radiation causes secondary tumours and/or enduring cognitive deficits, especially in children. Proton radiotherapy reduces exposure of the developing brain in children but may still cause some lasting effects. Recent observations show that ultra-high dose rate radiation treatment (!40 Gy/s), called the FLASH effect, is equally effective at tumour control but less damaging to surrounding tissue compared with conventional dose rate protons (0.03e3 Gy/s). Most studies on the FLASH effect in brain and other tissues with different radiation modalities (electron and photon radiation), show FLASH benefits in these preclinical rodent models, but the data are limited, especially for proton FLASH, including for dose, dose rate and neurochemical and neurobehavioural outcomes. Tests of neurocognitive outcomes have been limited despite clinical evidence that this is the area of greatest concern. The FLASH effect in the context of proton exposure is promising, but a more systematic and comprehensive approach to outcomes is needed.

Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model

“…There are several possibilities for the difference in NOR performance, such as the irradiation type, the species, age at irradiation, or the NOR protocol used in the study. The NOR test in radiation research and some of its limitations has been discussed [15]. NOR provides only a snapshot of incidental learning and does not provide information for other learning domains.…”

“…Recent studies suggest that high dose rates of radiation (>40 Gy/s; FLASH) may confer less toxicity to exposed healthy tissue and may reduce neurocognitive toxicity compared with conventional radiation dose rates (~1 Gy/s). Reduced toxicity in different organ systems from high dose rate radiation (the FLASH effect) has been tested on cell systems, zebrafish, cats, and humans [reviewed in [15]]. However, cognition after FLASH has mainly been tested in mice treated with either electrons or X-rays [16][17][18][19].…”

The Future of Radioactive Medicine

“…Though the field of radiopharmaceutical therapy has largely evolved into a subspecialty of the field nuclear medicine, it was historically an established methodology within conventional radiation therapy for treatment of a variety of cancers. 32 P for example, was first used in the 1930s for treatment of various hematological diseases including leukemia and polycythemia vera and 131 I in the 1940s for treatment of thyroid disease (40). Therapeutic use of these radionuclides are a few examples of radiopharmaceuticals used within radiation oncology even into modern times, though 32 P is no longer used for polycythemia vera due to the potential for leukemogenic/carcinogenic secondary side effects and has been largely replaced by other radiation therapy treatment modalities in treatment of other cancers (41,42).…”

It is beneficial to invest resources to implement proton intracranial SRS

“…Many times, we are discussing more than 8-10 lesions in one or multiple sessions, and therefore it is important that we review the dosimetric means by which we can treat multiple targets with protons when we have a multitude of photon modalities that can be used more than once to treat patients over the course of their disease management. In addition, as we explore the role of proton FLASH for the treatment of a number of malignancies, 46,47 does it make sense to spend money and time on a technique that may become obsolete before it can take off?…”