Neurobehavioral Late-Effects in Pediatric Brain Tumors

Principal Investigator: Mark Mahone

Radiation Therapy (RT) has been largely responsible for improving the survival rates of children with certain types of brain tumors, although this has come at a cost in terms of the neurodevelopment of these children. Continual modification of RT protocols relies upon accurate risk-benefit data coming from late-effects research. Variations to dose, volume, beam orientation, and fractionation schedule have now become integral in contemporary 3D conformal RT plans aimed at decreasing the toxic burden to normal tissue. Little is known, though, about the neurobehavioral risks associated with these modern radiation oncology methods since existing research is based on crude characterization of radiation parameters (i.e., prescribed dose, whole brain vs. focal RT). A potentially more precise index of the effect of radiation delivered to the whole brain or a treated volume can be obtained using dosimetry “mapping” methods and calculating the integral biologically effective dose (IBED), used here to condense the heterogeneous dose and volume information into a single value that can be used to rank biological effect of different RT treatments. Application of this “high definition” technique offers an unprecedented opportunity for improving the precision of RT late–effects research with the promise of informing the development of less neurotoxic RT protocols in the future. The benefits of such research are likely to be compounded when combined with recent developments in cognitive neuroscience that have elucidated the componential nature and corresponding neural infrastructure of critical neuropsychological processes, such as Attention, Working Memory and Processing Speed. Improved prediction and characterization of neurobehavioral effects could also lead to more refined early intervention strategies to reduce ultimate functional impairment. 

The overall goal of the proposal is to investigate whole brain and regional IBED in predicting brain and neurobehavioral late-effects of RT. To accomplish this, we propose using advanced imaging (volumetrics, spectroscopy, diffusion imaging) and neuropsychological measurement strategies in a three-center, prospective longitudinal design. 

First, to establish general risk parameters, the two-year neurobehavioral outcomes of children treated with RT for brain tumors will be compared to those treated with surgery only for tumors located in comparable brain regions.

Second, this will be followed by a series of analyses to investigate the relationships between IBED, imaging changes in brain structure/function, and changes in three vulnerable neuropsychological domains (Attention, Working Memory, and Processing Speed). The primary follow-up period will be two years post RT.