Fine Motor Skill Decline after Brain RT – A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial

Purpose Brain radiotherapy can impair fine motor skills (FMS). FMS are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for decline in FMS after fractionated brain RT. Methods On a prospective trial, 44 primary brain tumor patients received fractioned RT, underwent high-resolution volumetric MRI and diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], and Grooved Pegboard Dominant/Non-Dominant Hands [PDH/PNDH]) at baseline and 6 months post-RT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, 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 (LASSO) logistic regression, and random forests with nested cross-validation. Results Half of patients showed decline on PNDH, 17 of 42 (40.4%) on PDH, and 11 of 44 (25%) on DKEFS-TM. Automated bootstrapped logistic regression selected a one-term model including maximum dose to dominant postcentral white matter. LASSO selected this term and steroid use. The top five variables in random forest were all dosimetric: mean and maximum dose to dominant corticospinal tract; maximum dose to dominant thalamus; mean dose to dominant caudate; maximum dose to dominant postcentral white matter. This technique performed best with AUC 0.69 (95% CI 0.68 – 0.70) on nested cross-validation. Conclusion We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated ROIs correlated with decline in dominant hand fine motor dexterity in primary brain tumor patients, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the National Institutes of Health 1TL1TR001443, 1KL2TR001444, R01 CA238783-01 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee and the Institutional Review Board of UC San Diego/ Moores Cancer center gave ethical approval (IRB # 131457) for this work. The current manuscript reflects a secondary analysis of a prospective observational (non intervention) study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors