Eline Verhaak

Background: Both whole brain radiation therapy (WBRT) and Gamma Knife radiosurgery (GKRS) have shown efficacy in treating patients with multiple brain metastases (BM) with comparable survival. Effective treatments without negative cognitive side effects have become increasingly more important, as cognitive functions are crucial for daily functioning. Cognition and Radiation (CAR) Study B, aimed to compare cognitive outcomes in patients with 11-20 BM treated with either WBRT or GKRS. Methods: Patients with 11-20 newly diagnosed BM on a contrast-enhanced MRI-scan, expected survival >3 months, and Karnofsky Performance Status (KPS)≥70 were included at two Dutch hospitals and randomized 1:1 to WBRT or GKRS (stratification factors: age, histology, total BM volume, systemic treatment, KPS, and baseline Hopkins Verbal Learning total recall score (HVLT-R TR)). Cognitive functioning was measured at pre-treatment, and at 3, 6, 9, 12, and 15 months post-treatment. A decline of ≥5 points on the HVLT-R TR (immediate verbal memory) was considered a memory failure. Inclusion would be halted if the Bayesian posterior probability of a higher failure rate in one group versus the other exceeded 0.975 at 3 or 6 months post-treatment (interim monitoring). The trail is registered with ClinicalTrials.gov, Identifier: NCT02953717, and is closed for participation. Findings: In April 2022, after enrolment of 81 patients, an interim analysis was conducted. Inclusion was halted as the posterior probability of a higher memory failure rate in the WBRT group (40.6%) versus the GKRS group (12.5%) at 6 months (n=16 and n=21, respectively) exceeded the 0.975 threshold with a value of 0.978. Similarly, at other follow-ups, a pattern of higher posterior probabilities of cognitive decline was observed in the WBRT group compared to the GKRS group. Interpretation: The probability of cognitive decline was higher after WBRT versus GKRS. As preserving quality of life and cognitive functions is crucial, SRS should be considered as a treatment option for selected patients with up to 20 BM.

A data-centric approach prioritizing data quality enabled the development of a generalizable deep learning system that accurately detected and segmented brain metastases of all sizes on MRI scans.

Purpose: The aims of this study were to evaluate long-term multidimensional fatigue in patients with brain metastases (BM) up to 21 months after Gamma Knife radiosurgery (GKRS) and (change in) fatigue as predictor of survival.Methods: Patients with 1 to 10 BM, expected survival > 3 months, and Karnofsky Performance Status ≥ 70, and Dutch non-cancer controls were included. Fatigue was measured with the Multidimensional Fatigue Inventory. Levels of fatigue between patients and controls were compared using independent-samples t-tests. Linear mixed models were used to evaluate fatigue within the patient group up to 21 months after GKRS. Pre-GKRS fatigue and minimal clinically important (MCI) changes in fatigue in the first three months (defined as a 2-point difference) after GKRS were evaluated as predictors of survival time.Results: Prior to GKRS, patients with BM (n = 92) experienced significantly higher fatigue on all subscales than controls (n = 104). Over 21 months, physical fatigue increased, and mental fatigue decreased significantly. More specifically, general, and physical fatigue increased significantly between pre-GKRS and 3 months, followed by stable scores between 3 (n = 67) and 6 (n = 53), 6 and 12 (n = 34) and 12 and 21 (n = 21) months. An MCI increase in general or physical fatigue over the first 3 months after GKRS was a significant predictor of shorter survival time.Conclusion: Except for mental fatigue, all aspects of fatigue remained elevated or further increased up to 21 months after treatment. Furthermore, an increase in general or physical fatigue within three months after GKRS may be a prognostic indicator for poorer survival.ClinicalTrials.gov identifier: NCT02953756, November 3, 2016.

BACKGROUND: Survival rates have improved in the past years for patients with brain metastases (BMs).OBJECTIVE: To evaluate cognitive functioning and health-related quality of life (HRQoL) after Gamma Knife radiosurgery (GKRS) in a relatively large sample of long-term survivors.METHODS: Data from 38 long-term survivors (assessments available ≥ 12 mo post-GKRS) with, at time of enrollment, 1 to 10 newly diagnosed BMs, expected survival > 3 mo, and Karnofsky Performance Status ≥ 70 were analyzed. Cognitive functioning and HRQoL were assessed pre-GKRS (n = 38) and at 3 (n = 38), 6 (n = 37), 9 (n = 37), 12 (n = 34), 15 (n = 28), and 21 (n = 21) mo post-GKRS. The course of cognitive test performance and of HRQoL over time was analyzed using linear mixed models. Individual changes in cognitive performance and HRQoL from pre-GKRS to 21 mo were determined using reliable change indexes (RCIs) and clinical meaningful cutoffs, respectively.RESULTS: Cognitive performances and HRQoL of long-term survivors remained stable or improved up to 21 mo after GKRS. Improvements were found for immediate and delayed verbal memory, working memory, information processing speed, and emotional well-being. On the individual level, most patients had stable or improved test performances or HRQoL. For physical well-being only, most patients (47.6%) showed a decline (vs 28.6% improvement or 23.8% no change) from pre-GKRS until 21 mo post-GKRS.CONCLUSION: Up to 21 mo after GKRS, cognitive functioning and overall HRQoL improved or remained stable in long-term survivors. In long-term survivors with 1 to 10 BMs, GKRS did not cause (additional) cognitive deteriorations or declines in HRQoL at longer-term follow-up.

Purpose: Increasingly more patients with multiple (> 4) brain metastases (BM) are being treated with stereotactic radiosurgery (SRS). Preserving patients’ health-related quality of life (HRQoL) is an important treatment goal. The aim of this study was to assess (individual) changes in HRQoL in patients with 1–10 BM over time.Methods: A total of 92 patients were assessed before (n = 92) and at 3 (n = 66), 6 (n = 53), and 9 (n = 41) months after Gamma Knife radiosurgery (GKRS), using the Functional Assessment of Cancer Therapy-Brain (FACT-Br). The course of HRQoL was analyzed using linear mixed models. Clinical minimally important differences were used to evaluate individual changes.Results: At group level, patients’ physical well-being worsened, whereas emotional well-being improved over 9 months. Scores on other HRQoL subscales did not change significantly. Number (1–3 versus 4–10) and volume (small, medium, and large) of BM did not influence HRQoL over time, except for the subscale additional concerns; medium intracranial tumor volume was associated with less additional concerns. On the individual level as well, physical well-being declined while emotional well-being improved in most patients over 9 months after GKRS. At patient level, however, most patients had both declines as well as improvements in the different HRQoL aspects.Conclusion: Our results indicate that even in patients with up to 10 BM, both at group and individual subscale level, aspects of HRQoL remained stable over nine months after GKRS, except for an improvement in emotional well-being and a decline in physical well-being. Nevertheless, HRQoL scores varied considerably at the individual patient level.Trail registration number: ClinicalTrials.gov Identifier: NCT02953756, November 3, 2016.

Purpose: A growing number of patients with brain metastases (BM) are being treated with stereotactic radiosurgery (SRS), and the importance of evaluating the impact of SRS on the health-related quality of life (HRQoL) in these patients has been increasingly acknowledged. This systematic review summarizes the current knowledge about the HRQoL of patients with BM after SRS.Methods: We searched EMBASE, Medline Ovid, Web-of-Science, the Cochrane Database, PsycINFO Ovid, and Google Scholar up to November 15, 2018. Studies in patients with BM in which HRQoL was assessed before and after SRS and analyzed over time were included. Studies including populations of several types of brain cancer and/or several types of treatments were included if the results for patients with BM and treatment with SRS alone were described separately.Results: Out of 3638 published articles, 9 studies met the eligibility criteria and were included. In 4 out of 7 studies on group results, overall HRQoL of patients with BM remained stable after SRS. In small study samples of longer-term survivors, overall HRQoL remained stable up to 12 months post-SRS. Contradictory results were reported for physical and general/global HRQoL, which might be explained by the different questionnaires that were used.Conclusions: In general, SRS does not have significant negative effects on patients’ overall HRQoL over time. Future research is needed to analyze different aspects of HRQoL, differences in individual changes in HRQoL after SRS, and factors that influence these changes. These studies should take into account several methodological issues as discussed in this review.

Purpose Fatigue is a common and distressing symptom in cancer patients which negatively affects patients’ daily functioning and health-related quality of life. The aim of this study was to assess multidimensional fatigue in patients with brain metastases (BM) before, and after Gamma Knife radiosurgery (GKRS). Methods Patients with BM, an expected survival > 3 months, and a Karnofsky Performance Status ≥ 70 and 104 Dutch non-cancer controls were recruited. The Multidimensional Fatigue Inventory (MFI), measuring general fatigue, physical fatigue, mental fatigue, reduced activity and reduced motivation, was used. Baseline levels of fatigue between patients and controls were compared using independent-samples t-tests. The course of fatigue over time, and clinical and psychological predictors thereof, were analyzed using linear mixed models (within-group analyses). Results Ninety-two, 67 and 53 patients completed the MFI at baseline, and 3 and 6 months after GKRS. Before GKRS, patients with BM experienced significantly higher levels of fatigue on all subscales compared to controls (medium to large effect sizes). Over 6 months, general and physical fatigue increased significantly (p = .009 and p < .001), and levels of mental fatigue decreased significantly (p = .027). No significant predictors of the course of fatigue over time could be identified. Conclusions Fatigue is a major problem for patients with BM. Different patterns over time were observed for the various aspects of fatigue in patients with BM. Information on the various aspects of fatigue is important because fatigue may negatively affect patients' functional independence, health-related quality of life, and adherence to therapy.

Purpose Information on health-related quality of life (HRQoL) of patients with brain metastases (BM) before stereotactic radiosurgery (SRS) is very relevant to improve communication between patients and clinicians and to be able to interpret changes in HRQoL after SRS. The aim of this study was to evaluate the prevalence and severity of complaints on different aspects of pre-SRS HRQoL among patients with BM and to identify predictors thereof. Methods Patients with 1–10 newly diagnosed BM, expected survival > 3 months, Karnofsky Performance Status ≥ 70, and scheduled to undergo SRS were included. HRQoL was measured with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire. One-sample z-tests were conducted to analyze differences between patients with BM and published normative data of a general adult sample and of an adult cancer sample. Multiple regression analyses were run to identify predictors of pre-SRS HRQoL. Results On the individual level, most patients with BM (57.6% of 92 included patients) reported complaints regarding emotional well-being. As a group, patients with BM reported significantly lower emotional well-being compared to both control groups and significantly higher social well-being compared to the general population. Worse psychological factors, e.g. physical fatigue, depression, mental fatigue and anxiety, predicted aspects of pre-SRS HRQoL. Conclusions An increased understanding of pre-SRS HRQoL and predictors hereof, provides us with more insight into the well-being of our patients with BM and is necessary for the interpretation of (changes in) HRQoL after SRS.

Gamma Knife radiosurgery (GKRS) is increasingly applied in patients with multiple brain metastases and is expected to have less adverse effects in cognitive functioning than whole brain radiation therapy (WBRT). Effective treatment with the least negative cognitive side effects is increasingly becoming important, as more patients with brain metastases live longer due to more and better systemic treatment options. There are no published randomized trials yet directly comparing GKRS to WBRT in patients with multiple brain metastases that include objective neuropsychological testing. CAR-Study B is a prospective randomised trial comparing cognitive outcome after GKRS or WBRT in adult patients with 11–20 newly diagnosed brain metastases on a contrast-enhanced MRI-scan, KPS ≥70 and life expectancy of at least 3 months. Randomisation by the method of minimization, is stratified by the cumulative tumour volume in the brain, systemic treatment, KPS, histology, baseline cognitive functioning and age. The primary endpoint is the between-group difference in the percentage of patients with significant memory decline at 3 months. Secondary endpoints include overall survival, local control, development of new brain metastases, cognitive functioning over time, quality of life, depression, anxiety and fatigue. Cognitive functioning is assessed by a standardised neuropsychological test battery. Assessments (cognitive testing, questionnaires and MRI-scans) are scheduled at baseline and at 3, 6, 9, 12 and 15 months after treatment. Knowledge gained from this trial may be used to inform individual patients with BM more precisely about the cognitive effects they can expect from treatment, and to assist both doctors and patients in making (shared) individual treatment decisions. This trial is currently recruiting. Target accrual: 23 patients at 3-months follow-up in both groups. The Netherlands Trials Register number NTR5463. ClinicalTrials.gov registration number NCT02953717, first received October 27, 2016, 8 patients were enrolled in this study on 31 July 2017.