47 Cognitive Impact of SRS vs. WBRT: Systematic Review & Meta-analysis morphological changes after brain irradiation in both cortical structures (cortical thickness, grey matter volume, grey matter density) as well as white matter networks.58–64 Additionally, the amount of microstructural damage to white matter fibers has been shown to be directly associated with cognitive deterioration in cancer patients.65 Strengths and Limitations Cognitive functioning after cranial radiotherapy has been gaining research interest, as reflected by the included studies (published between 2003 and 2020), with most (9/14) published over the last five years. Nonetheless, studying cognitive changes after radiotherapy in patients with BMs remains challenging for multiple reasons. Firstly, different factors could influence cognitive functioning over the follow-up period, including tumor progression, adjuvant systemic treatment or changes in mood. Additionally, a substantial number of patients drop out during the study period, most often due to high disease burden. Especially in the long-term, results are therefore based on the small numbers of patients that are fit enough to stay compliant. Unfortunately, this is inevitable in this vulnerable patient population with limited overall survival. Additionally, numerous challenges hinder in-depth comparison across studies, including differences in patient characteristics (e.g. age), disease characteristics (e.g. primary tumor type) and treatment characteristics (radiotherapy schedule) of the study populations. For example, two studies investigated HA-WBRT (N = 149), while all others investigated conventional WBRT. We chose not to exclude these, since during HA-WBRT less brain tissue is irradiated and including this in the review would lead to an underrepresentation rather than an overrepresentation of the cognitive damage to be expected after WBRT compared to SRS. Also, there was much heterogeneity across studies regarding both the methodology (e.g. definition for cognitive impairment and decline, timing of cognitive testing) and reported data (e.g. baseline cognitive data). To illustrate, most studies did not control for practice effects due to repeated testing over time and only five out of fourteen studies reported using parallel test for the repeated neuropsychological testing, even though cognitive assessment was repeated up to nine times within a one-year period in some studies. These methodological shortcomings could have led to an underestimation of the cognitive changes after radiotherapy as cognitive problems might be masked by repeated testing effects. In order to aid comparability across studies, we chose to cluster the follow-up time points according to classifications used in previous studies. However, the subtle dynamics of cognitive change may not be ideally assessed by this classification. To illustrate, a difference in cognitive2
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