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.
Highlights
Radiation therapy (RT) is a critical component in the treatment of medulloblastoma (MB), which is the most common type of primary brain cancer in children [1]
The goal of this study was to investigate whether FLASH-RT would result in similar cognitive sparing in the young mice as described in studies which were published previously in adult mice [15]
We show that FLASH-RT results in marked neuroprotective properties compared to conventional dose rate irradiation in young mice
Summary
Radiation therapy (RT) is a critical component in the treatment of medulloblastoma (MB), which is the most common type of primary brain cancer in children [1]. The prevalence and persistence of these toxic radiotherapy side effects point to the deficiency of current therapies, where the resultant neural toxicities, stemming from the exquisite sensitivity of the juvenile brain to radiation exposure, define a distinct clinical challenge. These prolonged and debilitating disruptions to neurocognitive health are recognized as a major criterion for evaluating therapeutic outcomes and for determining long-term quality of life [9,10,11]
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