Eva Elisabeth van Grinsven

Background: Brain metastases (BMs) are often treated with stereotactic radiosurgery (SRS). Even with the high dose fall-off at tumor borders, some dose is delivered outside the BMs to ensure adequate tumor coverage. This may include radiation to the neurogenic niches (ie, subventricular zones [SVZ] and hippocampi), which possibly play a role in neurocognitive functioning (NCF). In this study, we assessed the impact of radiotherapy dose on the SVZ and hippocampi compared with changes in NCF 3 months post-SRS, focusing on memory and information processing speed (IPS) in adult patients with BMs. Methods: Neurocognitive assessments were performed before and 3 months post-SRS, and reliable change indices were calculated to assess NCF changes. The SVZ and hippocampal regions were delineated on pre-SRS T1-weighted MRI images and median radiotherapy dose per region was calculated. Results: Multivariable linear regression analyses in 36 patients corrected for age, previous brain radiotherapy, number of BMs, and previous systemic therapy indicated a significant association between higher hippocampal radiotherapy dose and decline in memory, specifically in Hopkins Verbal Learning Test-Revised immediate recall, delayed recall, and Rey Osterieth Complex Figure Test delayed copy (all P < .05). Conversely, no significant association was found between dose to the SVZ and memory, nor between dose to either region and IPS. Conclusions: These results suggest potential benefits of minimizing radiation exposure to the hippocampi, even with SRS, to help preserve memory in patients with BMs. Further prospective evaluation is warranted to validate these findings and inform clinical decision-making regarding radiotherapy protocols for preserving NCF in this patient population.

Background: Postoperative ischemia is a known complication of glioma resection that is registered by diffusion-weighted MRI (DWI) and can lead to new neurological deficits. The aim of this review was to assess the incidence of ischemia after glioma resection and identify potential risk factors and consequences. Methods: A systematic review was conducted according to the PRISMA guidelines. Cohort studies reporting surgeries for WHO grade II-IV gliomas followed by postoperative DWI within 72 h were included. Pooled, weighted incidences for postoperative ischemia and neurological deficits were calculated with a binary random-effects model. Results: In total, 29 studies were included in this review, of which 25 studies with 2729 cases were included for meta-analysis. Pooled incidence was 48% (95% confidence interval [CI]: 36%-59%) for postoperative ischemia and 32% (95% CI: 23%-41%) for postoperative transient and persistent neurological deficits. Postoperative ischemia with any neurological deficits occurred in 15% (95% CI: 10%-20%) of patients, postoperative ischemia without neurological sequelae in 26% (95% CI: 17%-35%), and 41% (95% CI: 30%-52%) of patients with postoperative ischemia experienced neurological deterioration. Postoperative ischemia was associated with opercular, insular, or temporal tumor locations, proximity to and infiltration of perforating arteries, prior radiotherapy, age and intraoperative hemodynamic decline, among others. Postoperative ischemia was related to neurological deterioration, recurrence, and overall survival in some studies. Conclusion: Postoperative ischemia is a quite frequent complication of glioma resection affecting functional outcome and disease progression. Potential risk factors may give insight in preventive measures and future studies with precise spatial analyses could identify vulnerable brain regions.

The increasing incidence of brain metastases (BMs) and improved survival rates underscore the necessity to investigate the effects of treatments on individuals. The aim of this study was to evaluate the individual trajectories of subjective and objective cognitive performance after radiotherapy in patients with BMs. The study population consisted of adult patients with BMs referred for radiotherapy. A semi-structured interview and comprehensive neurocognitive assessment (NCA) were used to assess both subjective and objective cognitive performance before, 3 months and ≥ 11 months after radiotherapy. Reliable change indices were used to identify individual, clinically meaningful changes. Thirty-six patients completed the 3-month follow-up, and 14 patients completed the ≥ 11-months follow-up. Depending on the domain, subjective cognitive decline was reported by 11–22% of patients. In total, 50% of patients reported subjective decline in at least one cognitive domain. Intracranial progression 3 months postradiotherapy was a risk-factor for self-reported deterioration (P = .031). Objective changes were observed across all domains, with a particular vulnerability for decline in memory at 3 months postradiotherapy. The majority of patients (81%) experienced both a deterioration as well as improvement (eg, mixed response) in objective cognitive functioning. Results were similar for the long-term follow-up (3 to ≥11 months). No risk factors for objective cognitive change 3 months postradiotherapy were identified. Our study revealed that the majority of patients with BMs will show a mixed cognitive response following radiotherapy, reflecting the complex impact. This underscores the importance of patient-tailored NCAs 3 months postradiotherapy to guide optimal rehabilitation strategies.

ObjectivePatients with brain metastases (BrMs) are a heterogeneous population, with almost 50% experiencing cognitive impairment before brain radiotherapy. Defining pre-radiotherapy cognitive profiles will aid in understanding of the cognitive vulnerabilities and offer valuable insight and guidance for tailoring interventions.MethodsThe study population consisted of 58 adult patients with BrMs referred for radiotherapy. A semi-structured interview and comprehensive battery including 10 neuropsychological tests were used to assess subjective and objective cognitive performance prior to radiotherapy.ResultsA majority (69%) of patients report decline in cognitive performance compared to their premorbid level (i.e. pre-cancer). Objective testing revealed memory (52%), processing speed (33%) and emotion recognition (29%) deficits were most frequent. 21% of patients had no cognitive deficits while 55% had deficits (-1.5SD) in at least two cognitive domains. Hierarchical cluster analysis based on patient deficit profiles identified four clusters: (I) no or limited cognitive deficits selectively restricted to processing speed or executive function, (II) psychomotor speed deficits, (III) memory deficits and (IV) extensive cognitive deficits including memory. No patient or clinical-related (e.g. age, number of BrMs, previous treatment) differences were found between clusters.ConclusionsPatterns of cognitive performance in patients with BrMs are heterogeneous, with most experiencing at least some degree of neurocognitive dysfunction. We identified four meaningful cognitive clusters. Stability of these clusters over time and in different samples should be assessed to advance understanding of the cognitive vulnerability of this patient population.

Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and this incidence is expected to rise due to advancements in primary tumor management. Besides improving survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/ The prospective COIMBRA study is designed to monitor a cohort of patients with BMs and their caregivers who are referred to a tertiary academic radiation oncology department (ClinicalTrials.gov Identifier: NCT05267158). The study is designed according to the Trials within Cohorts (TwiCs) framework, an adaptive design that allows for the evaluation of multiple interventions over time. Patients receive state of the art treatment, which includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Clinical data, QoL and cognitive functioning are collected at baseline and at regular intervals post-treatment. Additionally, new MRI techniques can be evaluated for their feasibility and performance in patients with BMs. PRELIMINARY Since April 2019, 419 patients have been included of whom 51.2% were men and the majority of the patients had lung cancer (53.6%). SRS was administered in 92.4% and 68.1% received systemic therapy. Median overall survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before treatment (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patients’ diagnosis. Our study successfully collected in-depth clinical and QoL data from patients with BMs and their caregivers. The results suggest a modest improvement in anxiety and QoL after SRS. These findings highlight the need for ongoing evaluation of interventions in this patient population in order to ultimately guide personalized treatment strategies.

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO₂) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO₂ within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (r_rm = −0.286, p < 0.001), CMRO₂ (r_rm = −0.254, p < 0.001), and CVR (r_rm = −0.346, p < 0.001), but not in OEF (r_rm = −0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, r_rm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF ( r_rm = −0.822) and longer arterial arrival time (AAT; r_rm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR ( r_rm = −0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.

Background & Objectives: Radiotherapy is standard treatment for patients with brain metastases (BMs), although it may lead to radiation-induced cognitive impairment. This review explores the impact of whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) on cognition. Methods: The PRISMA guidelines were used to identify articles on PubMed and EmBase reporting on objective assessment of cognition before, and at least once after radiotherapy, in adult patients with nonresected BMs. Results: Of the 867 records screened, twenty articles (14 unique studies) were included. WBRT lead to decline in cognitive performance, which stabilized or returned to baseline in patients with survival of at least 9–15 months. For SRS, a decline in cognitive performance was sometimes observed shortly after treatment, but the majority of patients returned to or remained at baseline until a year after treatment. Conclusions: These findings suggest that after WBRT, patients can experience deterioration over a longer period of time. The cognitive side effects of SRS are transient. Therefore, this review advices to choose SRS as this will result in lowest risks for cognitive adverse side effects, irrespective of predicted survival. In an already cognitively vulnerable patient population with limited survival, this information can be used in communicating risks and aid in making educated decisions.