Fine Motor Skill Decline After Brain Radiation Therapy-A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial

Abstract

Purpose: Brain radiation therapy can impair fine motor skills (FMS). Fine motor skills are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for the decline in FMS after fractionated brain radiation therapy (RT).

Methods and materials: On a prospective trial, 44 patients with primary brain tumors received fractioned RT; underwent high-resolution volumetric magnetic resonance imaging, diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS]; and Grooved Pegboard dominant/nondominant hands) at baseline and 6 months postRT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, cerebellum, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models using automated bootstrapped logistic regression, least absolute shrinkage and selection operator logistic regression, and random forests with nested cross-validation.

Results: Half of the patients showed a decline on grooved pegboard test of nondominant hands, 17 of 42 (40.4%) on grooved pegboard test of -dominant hands, and 11 of 44 (25%) on DKEFS-MS. Automated bootstrapped logistic regression selected a 1-term model including maximum dose to dominant postcentral white matter. The least absolute shrinkage and selection operator logistic regression selected this term and steroid use. The top 5 variables in the random forest were all dosimetric: maximum dose to dominant thalamus, mean dose to dominant caudate, mean and maximum dose to the dominant corticospinal tract, and maximum dose to dominant postcentral white matter. This technique performed best with an area under the curve of 0.69 (95% CI, 0.68-0.70) on nested cross-validation.

Conclusions: We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated regions of interest correlated with a decline in dominant-hand fine motor dexterity in patients with primary brain tumors in multivariate models, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT.

Trial registration: ClinicalTrials.gov NCT05576103.

Fig 1.

Heatmap for univariate logistic regression coefficient p-values for decline on PDH. Abbreviations: ROI: region of interest; dom: dominant; nondom: non-dominant; DVH: dose volume histogram; CST: corticospinal tract; D_max: maximum dose; D_mean: mean dose; WM: white matter; HS: high school; R: right (handedness); KPS: Karnofsky performance status; GTR: gross total resection; HGG: high grade glioma; AED: anti-epileptic drugs; chemo: chemotherapy; surgery_yn: yes vs no; rad type: radiation type.

Fig 2.

A) Frequency of variable selection over the cross-validation folds for the logistic methods. B) Variable importance in the random forest model by mean decrease in Gini score. Abbreviations: dom: dominant; nondom: non-dominant; DVH: dose volume histogram; CST: corticospinal tract; D_max: maximum dose; D_mean: mean dose; WM: white matter; HS: high school; R: right (handedness); KPS: Karnofsky performance status; GTR: gross total resection; HGG: high grade glioma; AED: anti-epileptic drugs; chemo: chemotherapy; surgery_yn: yes vs no; rad type: radiation type.

Fig 3.

Boxplots of area under the curve (AUC) performance over the repeated outer cross-validation held-out folds. Abbreviations: AUC: area under the curve; LASSO: least absolute shrinkage and selection operator