48 Chapter 2 deterioration-free survival of merely 0.7 months was found in favor of patients with resected BMs who received SRS (3.7 months) compared to WBRT (3 months).66 Thus, the time point clustering used in this study could have masked slight differences that are present between the SRS and WBRT patient groups. The heterogeneity between studies was also reflected by our meta-analysis on the incidence of cognitive decline over time; the meta-analysis indicated significant heterogeneity between studies regarding the reported incidence of cognitive decline for L&M at mid-term for the WBRT studies. This could be explained by the fact that the definition used to assess cognitive change varied greatly between studies and, moreover, was not always reported. Additionally, the meta-analysis shows relatively broad confidence intervals, due to the low number of patients for whom the data was available. Nonetheless, even with a small number of studies reporting the incidence of patients with cognitive decline, the meta-analysis indicated significant heterogeneity only for one type of radiotherapy, at one time-point and for one cognitive construct. In this review, 20 manuscripts reporting on 14 original datasets were included. We chose to include all 20 manuscripts since they answered different questions regarding cognitive functioning, thus did not present overlap. Results were summarized together per dataset to avoid overrepresentation of the same patients in this review. Strict inclusion criteria were used to minimize the potential confounding effects on cognitive performance (e.g. no resected BMs were included). Additionally, a critical appraisal was performed to ensure the quality of the data as reported in the manuscript, which indicated that the majority of the included studies (75%) was of good to high-quality. Therefore, we believe our conclusions are warranted. Future directions Currently, multiple single center trials are collecting and analyzing prospective data that will hopefully further improve our understanding of cognitive impairment after brain irradiation e.g. 67–70. Ideally, all future studies should at minimum use the neuropsychological tests recommended by the International Cancer and Cognition Task Force, since these tests have been proven to be sensitive to the neurotoxic effects of cancer treatment.71 A valuable line of research is to explore possible additional therapeutic strategies that could reduce treatment toxicity. As the mechanisms leading to radiation-induced cognitive impairment are multifactorial, several strategies, each addressing different mechanisms, have been proposed to potentially reduce the neurocognitive toxicity of radiation.72,73 For example,
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