Evidence-based multivariate normal tissue complication probability (ntcp) study of domain-specific cognitive decline after partial brain radiation (rt)

Abstract Beyond the hippocampus, there are no evidence-based dose constraints for eloquent brain structures which subserve cognitive domains. We performed a multivariate NTCP analysis of post-RT neurocognitive decline, examining dosimetric predictors of eloquent brain regions in a prospective longitudinal clinical trial. 83 patients with primary brain tumors receiving fractionated RT completed comprehensive neurocognitive evaluation and high-resolution volumetric and diffusion MRI at baseline and 6 months post-RT. Image processing using robust, validated automated segmentation parcellated individual white matter (WM) tracts, cortical regions, and hippocampi. Well-validated neurocognitive tests evaluating multiple cognitive domains were assessed with negative reliable change indices adjusted for practice effects between timepoints scored as decline. Univariate logistic regression and multivariate model building were performed examining dose to eloquent structures and clinical variables. Univariate analysis showed mean dose to the bilateral caudal anterior cingulate cortex and WM were correlated with decline in executive function. Attention/processing speed decline was correlated with mean/max dose to the posterior corpus callosum (CC), volume getting >20 Gy in the combined CC, as well as anti-epileptic use and chemotherapy. On multivariate analysis for attention automated bootstrapped logistic regression performance at nested cross-validation by AUC was 0.59 (0.54-0.65); LASSO model performance by AUC was 0.60 (0.54-0.66) with mean dose to combined CC being the most frequent variable in both. The top three most important variables in Random Forest by mean decrease in Gini coefficient were max dose to posterior and combined CC and mean dose to anterior CC. Model performance by AUC was 0.70 (0.64-0.75). Here we present the first, to our knowledge, NTCP model for decline in attention/processing speed, along with dosimetric predictors of executive function decline. We found that after partial brain RT, dose to several ROIs significantly correlated with post-RT impairment. These data can guide future cognitive-sparing strategies for brain RT.