214 Chapter 9 Large-scale studies have additionally shown premature brain aging and reduced gray matter volume in specific brain regions in patients with breast cancer who received chemotherapy.13 Similar accelerated brain aging has been observed after radiotherapy in patients with gliomas.14 This highlights the difficulty in interpreting post-radiotherapy brain changes and disentangling the exact contributions of one treatment. Thereby, the results presented in this thesis should be interpreted within the broader context of treatment-related side-effects in patients with BMs. Additionally, the post-radiotherapy changes presented in this thesis should be considered in light of the trade-off between cognitive difficulties and survival benefits after treatment. It is unclear what the cognitive trajectory would be of patients who do not receive radiotherapy. At the same time, research has shown that median survival is only two months for lung cancer patients with BMs who do not receive any treatment.15 Ideally, observational research in patients with BMs should include all patients, regardless of treatment choices. However, due to the multidisciplinary nature of BMs’ diagnosis, such a study can prove logistically complicated. In particular, locating patients who are not (yet) receiving radiation therapy can be challenging, as they may be under the care of a variety of medical specialties. Large national databases, such as those offered by the Integraal Kankercentrum Nederland (IKNL), possess the potential to facilitate such large-scale studies through their extensive data. However, BMs are not recorded as a distinct entity within the IKNL database. While information regarding the occurrence of BMs is documented on a per-primary cancer basis, there is a lack of comprehensive data on the overall BMs population, including details regarding treatment modalities and survival outcomes specific to this population. Consequently, the utilization of these databases for studying the BMs population becomes challenging. As such, large observational studies on BMs patients encompassing a diverse range of individuals are essential to either allow correction for treatment factors using statistical modeling or the possibility to create subgroups of adequate size for meaningful comparisons. This would allow researchers to piece together the intricacies of treatment-related changes in this patient population. An alternative option would be to create identical cohort studies including patients with primary tumors that commonly metastasize to the brain, such as breast, lung, and melanoma.16 The radiotherapy department at the University Medical Center Utrecht (UMCU) has made significant progress in creating extensive patient cohorts in various cancer populations, like the UMBRELLA cohort for breast cancer patients17 and the U-COLOR cohort for lung cancer patients (NCT05069792)18. However, these cohorts mainly focus on the medical aspects and quality of life (QoL) of patients,
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