Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment... Show moreTumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug–drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials. Show less
Glioma patients carry the burden of having both a progressive neurological disease and cancer, and may face a variety of symptoms, including depression and anxiety. These symptoms are highly... Show moreGlioma patients carry the burden of having both a progressive neurological disease and cancer, and may face a variety of symptoms, including depression and anxiety. These symptoms are highly prevalent in glioma patients (median point prevalence ranging from 16–41% for depression and 24–48% for anxiety when assessed by self-report questionnaires) and have a major impact on health-related quality of life and even overall survival time. A worse overall survival time for glioma patients with depressive symptoms might be due to tumor progression and/or its supportive treatment causing depressive symptoms, an increased risk of suicide or other (unknown) factors. Much is still unclear about the etiology of depressive and anxiety symptoms in glioma. These psychiatric symptoms often find their cause in a combination of neurophysiological and psychological factors, such as the tumor and/or its treatment. Although these patients have a particular idiosyncrasy, standard treatment guidelines for depressive and anxiety disorders apply, generally recommending psychological and pharmacological treatment. Only a few nonpharmacological trials have been conducted evaluating the efficacy of psychological treatments (eg, a reminiscence therapy-based care program) in this population, which significantly reduced depressive and anxiety symptoms. No pharmacological trials have been conducted in glioma patients specifically. More well-designed trials evaluating the efficacy of nonpharmacological treatments for depressive and anxiety disorders in glioma are urgently needed to successfully treat psychiatric symptoms in brain tumor patients and to improve (health-related) quality of life. Show less
Meer, P.B. van der; Maschio, M.; Dirven, L.; Taphoorn, M.J.B.; Koekkoek, J.A.F.; Italian League Epilepsy Brain Tumo 2022
Objective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients. Methods:... Show moreObjective: This study aimed to directly compare the effectiveness of first-line monotherapy levetiracetam (LEV) versus enzyme-inducing antiseizure medications (EIASMs) in glioma patients. Methods: In this nationwide retrospective observational cohort study, Grade 2-4 glioma patients were included, with a maximum duration of follow-up of 36 months. Primary outcome was antiseizure medication (ASM) treatment failure for any reason, and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariate cause-specific cox proportional hazard models were estimated, adjusting for potential confounders. Results: In the original cohort, a total of 808 brain tumor patients with epilepsy were included, of whom 109 glioma patients were prescribed first-line LEV and 183 glioma patients first-line EIASMs. The EIASM group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR] = 1.82, 95% confidence interval [CI] = 1.20-2.75, p = .005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR = 1.32, 95% CI = .78-2.25, p = .300), but treatment failure due to adverse effects differed significantly (aHR = 4.87, 95% CI = 1.89-12.55, p = .001). Significance: In this study, it was demonstrated that LEV had a significantly better effectiveness (i.e., less ASM treatment failure for any reason or due to adverse effects) compared to EIASMs, supporting the current neuro-oncology guideline recommendations to avoid EIASMs in glioma patients. Show less
Meer, P.B. van der; Taphoorn, M.J.B.; Koekkoek, J.A.F. 2022
Purpose of reviewA concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic... Show morePurpose of reviewA concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).Recent findingsIsocitrate dehydrogenase mutation and its active metabolite d-2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naive BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.SummaryManagement of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted. Show less
Koekkoek, J.A.F.; Meer, P.B. van der; Pace, A.; Hertler, C.; Harrison, R.; Leeper, H.E.; ... ; Walbert, T. 2022
Background This systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for... Show moreBackground This systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for palliative care in adults with malignant brain tumors. It provides an overview of palliative care options, including during the end-of-life phase for patients with malignant brain tumors. Methods A systematic literature search was conducted from 2016 to 2021 focusing on four main topics: (1) symptom management, (2) caregiver needs, (3) early palliative care, and (4) care in the end-of-life phase. An international panel of palliative care experts in neuro-oncology synthesized the literature and reported the most relevant updates. A total of 140 articles were included. Results New insights include that: Hippocampal avoidance and stereotactic radiosurgery results in a lower risk of neurocognitive decline in patients with brain metastases; levetiracetam is more efficacious in reducing seizures than valproic acid as first-line monotherapy antiseizure drug (ASD) in glioma patients; lacosamide and perampanel seem well-tolerated and efficacious add-on ASDs; and a comprehensive framework of palliative and supportive care for high-grade glioma patients and their caregivers was proposed. No pharmacological agents have been shown in randomized controlled trials to significantly improve fatigue or neurocognition. Conclusions Since the 2017 EANO palliative care guidelines, new insights have been reported regarding symptom management and end-of-life care, however, most recommendations remain unchanged. Early palliative care interventions are essential to define goals of care and minimize symptom burden in a timely fashion. Interventional studies that address pain, fatigue, and psychiatric symptoms as well as (the timing of) early palliative care are urgently needed. Show less
Koekkoek, J.A.F.; Meer, P.B. van der; Pace, A.; Hertler, C.; Harrison, R.; Leeper, H.E.; ... ; Walbert, T. 2022
BackgroundThis systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for... Show moreBackgroundThis systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for palliative care in adults with malignant brain tumors. It provides an overview of palliative care options, including during the end-of-life phase for patients with malignant brain tumors.MethodsA systematic literature search was conducted from 2016 to 2021 focusing on four main topics: (1) symptom management, (2) caregiver needs, (3) early palliative care, and (4) care in the end-of-life phase. An international panel of palliative care experts in neuro-oncology synthesized the literature and reported the most relevant updates. A total of 140 articles were included.ResultsNew insights include that: Hippocampal avoidance and stereotactic radiosurgery results in a lower risk of neurocognitive decline in patients with brain metastases; levetiracetam is more efficacious in reducing seizures than valproic acid as first-line monotherapy antiseizure drug (ASD) in glioma patients; lacosamide and perampanel seem well-tolerated and efficacious add-on ASDs; and a comprehensive framework of palliative and supportive care for high-grade glioma patients and their caregivers was proposed. No pharmacological agents have been shown in randomized controlled trials to significantly improve fatigue or neurocognition.ConclusionsSince the 2017 EANO palliative care guidelines, new insights have been reported regarding symptom management and end-of-life care, however, most recommendations remain unchanged. Early palliative care interventions are essential to define goals of care and minimize symptom burden in a timely fashion. Interventional studies that address pain, fatigue, and psychiatric symptoms as well as (the timing of) early palliative care are urgently needed. Show less
Background The feasibility of implementing an advance care planning (ACP) program in daily clinical practice for glioblastoma patients is unknown. We aimed to evaluate a previously developed... Show moreBackground The feasibility of implementing an advance care planning (ACP) program in daily clinical practice for glioblastoma patients is unknown. We aimed to evaluate a previously developed disease-specific ACP program, including the optimal timing of initiation and the impact of the program on several patient-, proxy-, and care-related outcomes. Methods The content and design of the ACP program were evaluated, and outcomes including health-related quality of life (HRQoL), anxiety and depression, and satisfaction with care were measured every 3 months over 15 months. Results Eighteen patient-proxy dyads and two proxies participated in the program. The content and design of the ACP program were rated as sufficient. The preference for the optimal timing of initiation of the ACP program varied widely, however, most of the participants preferred initiation shortly after chemoradiation. Over time, aspects of HRQoL remained stable in our patient population. Similarly, the ACP program did not decrease the levels of anxiety and depression in patients, and a large proportion of proxies reported anxiety and/or depression. The needed level of support for proxies was relatively low throughout the disease course, and the level of feelings of caregiver mastery was relatively high. Overall, patients were satisfied with the provided care over time, whereas proxies were less satisfied in some aspects. Conclusions The content and design of the developed disease-specific ACP program were rated as satisfactory. Whether the program has an actual impact on patient-, proxy-, and care-related outcomes proxies remain to be investigated. Show less
Coomans, M.; Dirven, L.; Aaronson, N.; Baumert, B.G.; Bent, M. van den; Bottomley, A.; ... ; EORTC Brain Tumor Grp 2022
Background: Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related... Show moreBackground: Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. Methods: We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Results: Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on >= 1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. Conclusions: HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients' functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled. Show less
Background: Neurocognitive impairments are common among brain tumor patients, and may impact patients' awareness of performance in instrumental activities in daily life (IADL). We examined... Show moreBackground: Neurocognitive impairments are common among brain tumor patients, and may impact patients' awareness of performance in instrumental activities in daily life (IADL). We examined differences between patient- and proxy-reported assessments of the patient's IADL, and whether the level of (dis)agreement is associated with neurocognitive impairments. Methods Brain tumor patients and their proxies completed the phase 3 version of the EORTC IADL-BN32 questionnaire measuring IADL, and patients completed six neurocognitive measures. Patient-proxy difference scores in IADL were compared between patients who were defined as neurocognitively impaired (>= 2 neurocognitive measures >= 2.0 standard deviations below healthy controls) and non-neurocognitively impaired. With multinomial logistic regression analyses we examined if neurocognitive variables were independently associated with patient-proxy disagreement in IADL ratings. Results Patients (n = 81) did not systematically (P < .01) rate IADL outcomes different than their proxies. Proxies did report more problems on 19/32 individual items and all five scales. This effect was more apparent in dyads with a neurocognitively impaired patient (n = 37), compared to dyads with non-neurocognitively impaired patients (n = 44). Multinomial logistic regression analyses showed that several neurocognitive variables (e.g., cognitive flexibility and verbal fluency) were independently associated with disagreement between patients and proxies on different scales. Conclusion Neurocognitive deficits seem to play a role in the discrepancies between brain tumor patients and their proxies assessment of patient's level of IADL. Although replication of our results is needed, our findings suggests that caution is warranted in interpreting self-reported IADL by patients with neurocognitive impairment, and that such self-reports should be supplemented with proxy ratings. Show less
Background: Glioma patients may experience behavioral and personality changes (BPC), negatively impacting their lives and that of their relatives. However, there is no clear definition of BPC for... Show moreBackground: Glioma patients may experience behavioral and personality changes (BPC), negatively impacting their lives and that of their relatives. However, there is no clear definition of BPC for adult glioma patients, and here we aimed to determine which characteristics of BPC are relevant to include in this definition.Methods: Possible characteristics of BPC were identified in the literature and presented to patients and (former) caregivers in an online survey launched via the International Brain Tumour Alliance. Participants had to rate the relevance of each presented characteristic of BPC, the three characteristics with the most impact on their lives, and possible missing characteristics. A cluster analysis and discussions with experts provided input to categorize characteristics and propose a definition for BPC.Results: Completed surveys were obtained from 140 respondents; 35% patients, 50% caregivers, and 15% unknown. Of 49 proposed characteristics, 35 were reported as relevant by at least 25% (range: 7%-44%) of respondents. Patients and caregivers rated different characteristics as most important. Common characteristics included in the top 10 of both patients and caregivers were lack of motivation, change in being socially active, not able to finish things, and change in the level of irritation. No characteristics were reported missing by >= 5 respondents. Three categories of BPC were identified: (1) emotions, needs, and impulses (2) personality traits, and (3) poor judgement abilities.Conclusion: The work resulted in a proposed definition for BPC in glioma patients, for which endorsement from the neuro-oncological community will be sought. A next step is to identify or develop an instrument to evaluate BPC in glioma patients. Show less
Background: Comprehensive data on the efficacy and tolerability of antiepileptic drugs (AED) treatment in glioma patients with epilepsy are currently lacking. In this systematic review, we... Show moreBackground: Comprehensive data on the efficacy and tolerability of antiepileptic drugs (AED) treatment in glioma patients with epilepsy are currently lacking. In this systematic review, we specifically assessed the efficacy of AEDs in patients with a grade II-IV glioma.Methods: Electronic databases PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane Library were searched up to June 2020. Three different outcomes for both mono- and polytherapy were extracted from all eligible articles: (i) seizure freedom; (ii) >= 50% reduction in seizure frequency; and (iii) treatment failure. Weighted averages (WA) were calculated for outcomes at 6 and 12 months.Results: A total of 66 studies were included. Regarding the individual outcomes on the efficacy of monotherapy, the highest seizure freedom rate at 6 months was with phenytoin (WA = 72%) while at 12-month pregabalin (WA = 75%) and levetiracetam (WA = 74%) showed highest efficacy. Concerning >= 50% seizure reduction rates, levetiracetam showed highest efficacy at 6 and 12 months (WAs of 82% and 97%, respectively). However, treatment failure rates at 12 months were highest for phenytoin (WA = 34%) and pregabalin (41%). When comparing the described polytherapy combinations with follow-up of >= 6 months, levetiracetam combined with phenytoin was most effective followed by levetiracetam combined with valproic acid.Conclusion: Given the heterogeneous patient populations and the low scientific quality across the different studies, seizure rates need to be interpreted with caution. Based on the current limited evidence, with the ranking of AEDs being confined to the AEDs studied, levetiracetam, phenytoin, and pregabalin seem to be most effective as AED monotherapy in glioma patients with epilepsy, with levetiracetam showing the lowest treatment failure rate, compared to the other AEDs studied. Show less
Background. The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be... Show moreBackground. The Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.Methods. A systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.Results. A total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORT QLQ-C30 and QLQ-BN20 (n = 286 and n = 247),and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).Conclusion. Many different PRO measures assessing symptoms, (I)ADL or HROoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their wales/items exhibit good content validity and other measurement properties for use in brain tumor patients. Show less
Background. Minimally important differences (MIDs) allow interpretation of the clinical relevance of health-related quality of life (HRQOL) results. This study aimed to estimate MIDs for all... Show moreBackground. Minimally important differences (MIDs) allow interpretation of the clinical relevance of health-related quality of life (HRQOL) results. This study aimed to estimate MIDs for all European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) scales for interpreting group-level results in brain tumor patients.Methods. Clinical and HRQOL data from three glioma trials were used. Clinical anchors were selected for each EORTC QLQ-C30 scale, based on correlation (>0.30) and clinical plausibility of association. Changes in both HRQOL and the anchors were calculated, and for each scale and time period, patients were categorized into one of the three clinical change groups: deteriorated by one anchor category, no change, or improved by one anchor category. Mean change method and linear regression were applied to estimate MIDs for interpreting within-group change and between-group differences in change over time, respectively. Distribution-based methods were applied to generate supportive evidence.Results. A total of 1687 patients were enrolled in the three trials. The retained anchors were performance status and eight Common Terminology Criteria for Adverse Events (CTCAE) scales. MIDs for interpreting within-group change ranged from 4 to 12 points for improvement and -4 to -14 points for deterioration. MIDs for between-group difference in change ranged from 4 to 9 for improvement and -4 to -16 for deterioration. Most anchor-based MIDs were closest to the 0.3 SD distribution-based estimates (range: 3-10).Conclusions. MIDs for the EORTC QLQ-C30 scales generally ranged between 4 and 11 points for both within-group mean change and between-group mean difference in change. These results can be used to interpret QLQ-C30 results from glioma trials. Show less
Simple Summary: Health-related quality of life (HRQoL) is an important outcome in glioma patients, as it reflects the patient's perspective on their functioning and wellbeing through the disease... Show moreSimple Summary: Health-related quality of life (HRQoL) is an important outcome in glioma patients, as it reflects the patient's perspective on their functioning and wellbeing through the disease course. The aim of our systematic review was to provide an overview of how HRQoL data is currently analyzed and interpreted in glioma studies. We found that the number of studies including HRQoL data increased in the past decade, but that assessment and analytical methods were highly variable. Ways to maximize information obtained with HRQoL questionnaires include appropriate and complementary analyses at both the group and individual level, comprehensive reporting of HRQoL results, and adherence to existing guidelines on the assessment, analysis, reporting and interpretation of patient-reported outcomes. This may ultimately result in high quality information that is relevant to inform physicians, patients and their relatives about the impact of the disease and its treatment on the patients' functioning and well-being.Background: Health-related quality of life (HRQoL) has become an increasingly important patient-reported outcome in glioma studies. Ideally, collected HRQoL data should be exploited to the full, with proper analytical methods. This systematic review aimed to provide an overview on how HRQoL data is currently evaluated in glioma studies, focusing on the research objectives and statistical analyses of HRQoL data. Methods: A systematic literature search in the databases PubMed, Embase, Web of Science and Cochrane was conducted up to 5 June 2020. Articles were selected based on predetermined inclusion criteria and information on study design, HRQoL instrument, HRQoL research objective and statistical methods were extracted. Results: A total of 170 articles describing 154 unique studies were eligible, in which 17 different HRQoL instruments were used. HRQoL was the primary outcome in 62% of the included articles, and 51% investigated >= 1 research question with respect to HRQoL, for which various analytical methods were used. In only 42% of the articles analyzing HRQoL results over time, the minimally clinical important difference was reported and interpreted. Eighty-six percent of articles reported HRQoL results at a group level only, and not at the individual patient level. Conclusion: Currently, the assessment and analysis of HRQoL outcomes in glioma studies is highly variable. Opportunities to maximize information obtained with HRQoL data include appropriate and complementary analyses at both the group and individual level, comprehensive reporting of HRQoL results in separate articles or supplementary material, and adherence to existing guidelines about the assessment, analysis and reporting of patient-reported outcomes. Show less
Background. Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods... Show moreBackground. Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods to evaluate change in HRQoL and to study whether these methods result in different conclusions.Methods. HRQoL data from 15 randomized clinical trials were combined (CODAGLIO project). Change in HRQoL scores, measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and BN20 questionnaires, was analyzed in 3 ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms, (2) at the patient level per scale/item, calculating the percentage of patients that deteriorated, improved, or remained stable per scale/item, and (3) at the individual patient level, combining all scales/items.Results. Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level, only the item "hair loss" showed a significant and clinically relevant change (ie, >= 10 points) over time, whereas change scores on the other scales/items were statistically significant only (all P <.001; range in change score, 0.1-6.2). Although a large proportion of patients had stable HRQoL over time (range, 27%-84%) on the patient level per scale/item, many patients deteriorated (range, 6%-43%) or improved (range, 8%-32%) on a specific scale/item. At the individual patient level, the majority of patients (86%) showed both deterioration and improvement, whereas only 1% remained stable on all scales.Conclusions. Different analytical methods of changes in HRQoL result in distinct conclusions of treatment effects, all of which may be relevant for informing clinical decision making. Show less
