215 Discussion but do not include specific measures of cognitive functioning. While some other research groups have investigated these populations, cross-study comparisons are hampered by differences in methodological set-up and limited reported data as we observed in Chapter 2. Performing identical neurocognitive assessments (NCA) and brain imaging at similar follow-up intervals in cohort studies in these patient populations could be a valuable, yet realistic avenue to further elucidate cancer treatment-related side-effects in patients with BMs. In the first place, the implementation of such long-term cohort studies would provide the chance to capture and evaluate all patients who eventually develop BMs, irrespective of subsequent treatment choices. Moreover, this approach would facilitate insights into the cognitive trajectory of patients with BMs prior to initializing brain radiotherapy. Lastly, it would provide an opportunity to assess the validity and generalizability of cognitive clusters, like those identified in Chapter 3, across different patient populations and/or after different treatment regimens. Various influences on behavior Countless factors influence neurocognitive functioning in patients with BMs. Thereby the most obvious influence is of course the BMs themselves. The brain can be topologically organized with respect to brain function, whereby lesions in two different locations each have a different effect on subsequent behavior.19 This probably partly explains the different cognitive profiles that we found in patients with BMs before starting radiotherapy in Chapter 3. That is, BMs within the memory network may specifically cause memory problems, while a BMs in the language network may specifically cause language problems. In Chapter 6 we additionally found out that on top of this, the etiology causing the lesions influences resulting behavior, highlighting the importance of population-specific research. The influence of systemic treatment on neurocognitive functioning has received more and more attention over the last years. However, it is less well-known that both cognitive and affective disorders are already prevalent in patients with non-central nervous system tumors before starting systemic treatment.20 This indicates that the presence of a primary tumor already exerts an influence on the brain leading to cognitive deficits. On top of that, the psychological distress associated with a cancer diagnosis and treatment has been found to have a detrimental effect on cognition. For example, in patients with BMs who received whole-brain radiotherapy (WBRT), increased psychological distress after WBRT was related to decreased cognitive performance and decreased QoL.21 Research has even demonstrated a relationship between stress and structural changes in various brain regions.20,22 Together, this illustrates it is crucial for researchers to consider the broader context in which 9
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