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Radiation therapy (RT) is a fundamental part of treatment for brain tumours.  Unfortunately, RT may be associated with neurocognitive impairment, and, in recent years, RT to the hippocampus has been investigated due to its important function in learning and memory. However, the relationship between RT dose and effects on neurocognitive function, have not been clearly established. The primary aim of this study was to examine if patients who had received high RT doses to the hippocampus would show impairment on the Hopkins Verbal Learning Test (HVLT) – a test of verbal learning and memory.  A second aim was to elucidate relationships between RT dose to the whole brain, thalamus, left, right, and total hippocampus, temporal and frontal lobes, and neurocognitive function based on a priori hypothesized structure-function relationships.

Neurocognitive function was assessed cross-sectionally in 78 progression-free patients with a primary brain tumour grade I-III or medulloblastoma treated with RT between 2007 and 2016. RT was administered in 1.8-2.0 Gy per fraction with total doses ranging from 45-60 Gy. Doses were converted to biologically equivalent doses in 2 Gy fractions (EQD₂) assuming an α/β ratio of 3 Gy. Dose Volume Histograms were generated for the delineated structures. Neurocognitive function was assessed a median of 4.6 years after completion of RT with a battery of 7 neuropsychological tests covering multiple neurocognitive domains. Results were converted to z-scores using available normative data adjusted for age and, when available, level of education. Domain-specific impairment was defined as a z-score ≤ -1.5 standard deviation (SD).

To examine the effect of doses to various brain structures and their function, mean EDQ₂ to the structure and test z-scores as a binary outcome variables were fitted to a logistic regression model. A p-value < 0.05 was considered significant. Domain-specific neurocognitive impairment was evident in the entire group of patients. High mean EQD₂ to the left hippocampus was associated with verbal learning and memory impairment (p=0.04). High mean EQD₂ to the left hippocampus (p=0.03), left temporal lobe (p=0.04), left frontal lobe (p<0.01), and total frontal lobe (p=0.02) were associated with verbal fluency impairment (figure 1). High mean EQD₂ to left frontal lobe (p=0.01) and thalamus (p=0.03) were associated with impairment in executive function (p=0.01). High mean EQD₂ to the total brain (p=0.05) and thalamus (p=0.02) were associated with processing speed impairment.

The present study finds associations between impaired performance in verbal learning and memory, verbal fluency, executive function and processing speed, in patients who had received RT to left hippocampus and temporal lobe, left frontal lobe, thalamus and the total brain. Validation of these findings is being undertaken in a prospective study that will include pre-treatment neurocognitive assessment.