28 Chapter 2 with non-resected BMs to gain insight on whether current evidence regarding cognitive side-effects substantiate contemporary shifts in treatment preference. METHODS Search Strategy The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in conducting and reporting this systematic review.17 We reviewed all published manuscripts on the neurocognitive effects of WBRT or SRS in adult patients with BMs from 1-1-1950 until 4-1-2021. The search strategy combined terms for BMs, radiotherapy and cognition, and was developed for PubMed and adapted for Embase. The complete search strings can be found in the Supplementary Materials. Additionally, reference lists were manually screened for potentially relevant studies. Manuscripts were screened by two researchers (EEvG & SHJN) and disagreement was resolved through consensus meetings. The screening of the studies was facilitated by Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). Reasons for exclusion were documented for each paper. Eligibility The search was confined to manuscripts in English and Dutch. Studies were selected in which objective neurocognitive assessment was performed at baseline (defined as any time point between presentation of the BMs and start of radiotherapy), and at least once after radiotherapy, in adult patients with BMs. Only objective cognitive measurements were included since self-reports may be biased due to impairments caused by the BMs and (previous) cancer treatments.18 Moreover, subjective cognitive complaints do not represent underlying cognitive deficits per se and may be more indicative of psychological distress than actual cognitive impairment.19,20 Studies solely utilizing short neurocognitive-screening tools, such as the Mini-Mental Status Examination (MMSE), were excluded since these tests lack the sensitivity to detect subtle changes in cognitive functioning expected to be present after radiotherapy.21–23 Furthermore, all papers including patients with resected BMs were excluded since co-acting cortical tissue damage adjacent to the resection site can influence cognitive performance. Studies investigating the influence of treatments concurrent to radiotherapy (e.g. memantine) that did not report on a radiotherapy-only control group were also excluded. Case reports, reviews, commentaries, editorials and protocols were excluded. If multiple papers reported on the same dataset, the results were combined and reviewed as one cohort.
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