Piecing the puzzle together
Authors:   , van Grinsven Eva Elisabeth 
Published: March 2024

Brain metastases (BMs) affect a growing proportion of adult cancer patients. The focus of patient-centered treatment has shifted towards balancing prolongation of life with quality of life. One of the cornerstones of medical treatment for BMs is radiotherapy. However, despite efforts to minimize radiation's impact on healthy brain tissue, cognitive decline remains common due to radiation-induced brain injury, with unclear underlying mechanisms. In the pursuit of providing optimal care, an integrative and multidisciplinary approach is not only essential in clinical practice, but also in research. This multidisciplinary thesis aims to set the first steps by simultaneously exploring neurocognitive functioning and the potential value of several MRI-biomarkers, this research can advance our understanding and pave the way for improved patient outcomes in the field of BMs radiotherapy.

In Part I, we investigated neurocognitive functioning in patients with BMs. When comparing the prominent strategies for radiotherapy, stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT), SRS is favored for its precise targeting of BMs. In Chapter 2 we performed a meta-analysis to compare SRS with WBRT, and revealed a decline in cognitive performance after WBRT, whereas SRS showed transient effects, supporting the preference for SRS to minimize persistent cognitive issues. In Chapter 3 we found heterogenous cognitive profiles prior to radiotherapy, with memory deficits being a significant factor. Elaborate testing proved essential in identifying the extent of cognitive deficits. Chapter 4 found prevalent post-radiotherapy cognitive decline up to 12 months, with concurrent improvement in some patients, but no clear risk factors emerged, underlining the complexity of underlying mechanisms.

To aid in understanding of the pathophysiology underlying the cognitive difficulties, part II focused on imaging techniques to understand the cognitive variation. An important factor may be the location of the BMs. However, lesion-symptom mapping (LSM) studies in the BMs population are complicated by numerous factors, while the generalizability of previous LSM results from other populations remains unclear. Therefore, in Chapter 5 we compared LSM between ischemic stroke and primary brain tumor patients. The findings highlighted the influence of lesion etiology on cognitive consequences, cautioning against generalization across populations. Consequently, we searched for possible other MRI-biomarkers that could aid in understanding the cognitive variation. In Chapter 6, we found a correlation between hypercapnic blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) metrics. This relationship, however, is dependent on vascular status of the underlying tissue. Thereby, BOLD-CVR metrics exhibited potential to identify vascular risk in tissue prior to visible perfusion deficits on ASL-MRI. Preliminary analysis in Chapter 7 suggested minimal impact of radiotherapy on metabolic and vascular reserves within three months post-treatment, with varying effects in high-dose regions. This study highlights the parameters' possible susceptibility to identify both restoration of or ongoing metabolic and vascular damage following radiotherapy, with a first cautious link to cognitive changes.

Summarizing, BMs pose complex challenges in treatment and understanding cognitive outcomes. While treatment advancements enhance survival, cognitive decline remains concerning. Further research integrating multiple MRI-biomarkers is crucial to elucidate underlying mechanisms and optimize treatment strategies for improved patient outcomes.