Fiscal Year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: “Pediatric brain tumors” and “Pediatric, adolescent, and young adult cancers”

Objective: Although advances in diagnosis and treatment have dramatically increased the survival rates for children and adolescents with brain tumors, side effects from treatment remain a major problem. The ability to remember new information (memory) and complete mental tasks in a timely fashion (processing speed) are particularly affected in children and adolescents who are treated with radiation therapy (RT). We will directly address this important problem by: (1) investigating new ways to selectively reduce RT dose to parts of the brain (i.e., substructures) that are important for memory and processing speed while treating the tumor, and (2) studying the timeline of injury to white matter pathways in the brain that we think are particularly vulnerable to cancer treatment using diffusion-weighted magnetic resonance imaging.

Rationale: We have previously shown that reducing RT dose to parts of the brain responsible for memory and processing speed is associated with improved performance on tests of memory and processing speed in children. We and others have also shown that there is white matter injury prior to RT in children who have undergone surgery, highlighting the importance of studying white matter pathways that connect the area of injury to the area of tumor.

Relevance to Behavioral Health Science Award: The intent of the Behavioral Health Science Award is to “advance behavioral health cancer science and fill gaps in the understanding of survivorship.” A key gap in knowledge for childhood survivors of brain tumors is how to reduce neurocognitive deficits in memory and processing speed, which have a significant impact on social-emotional well-being, academic performance, and the ability to live independently as an adult. Our proposal directly addresses this gap by testing novel RT strategies to reduce these deficits and by investigating the relationships between early and late white matter injury, RT dose, and neurocognitive outcomes. Furthermore, our innovative and high-reward study will shift the paradigm of RT planning from one that is substructure naïve to one that is substructure informed. Historically, the brain has been treated as a single homogeneous unit in RT planning, and substructures have not been used to optimize plans. Substructure-informed RT planning will limit RT injury to substructures that are highly susceptible to RT damage and critical for neurocognitive function, potentially reducing both the acute and long-term neurocognitive deficits.

FY22 PPRC Overarching Challenge and How it Will Make an Impact: This proposal addresses the following FY22 PRCRP Overarching Challenge: “Develop strategies to reduce short- and long-term treatment effects, including neurocognitive deficits.” Our first objective described above will reduce short-term neurocognitive deficits in memory and processing speed. Our second objective will investigate the relationship between early/late white matter injury and acute/long-term neurocognitive deficits. By deepening our understanding of white matter injury and selectively limiting dose to parts of the brain that are important for memory and processing new information, we believe we can preserve the cognitive ability of children undergoing RT therapy, which in turn will lead to better performance in school, better relationships with Family and friends, and an overall improved quality of life. This will have an impact on a large proportion of children with cancer, because brain tumors represent the most common solid malignancy in children, and RT therapy is often required for cure.