External validation of the lung-molGPA to predict survival in patients treated with stereotactic radiotherapy for brain metastases of non-small cell lung cancer.

BACKGROUND: In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. MATERIALS AND METHODS: Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). RESULTS: The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. CONCLUSION: The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

Impact of timing of antiseizure medication withdrawal on seizure recurrence in glioma patients: a retrospective observational study.

BACKGROUND: Withdrawal of antiseizure medication treatment (ASM) can be considered after completion of antitumour treatment in glioma patients who no longer suffer from seizures. We compared the risk for recurrent seizures after ASM withdrawal between patients with short-term, medium-term versus long-term seizure freedom after antitumour treatment. METHODS: In this retrospective observational study, the primary outcome was time to recurrent seizure, from the starting date of no ASM treatment up to 36 months follow-up. Cox proportional hazards models were used to study the effect of risk factors on time to recurrent seizure. Stratification was done with information known at baseline. Short-term seizure freedom was defined as ≥ 3 months, but < 12 months; medium-term as 12-24 months; and long-term as ≥ 24 months seizure freedom from the date of last antitumour treatment. RESULTS: This study comprised of 109 patients; 31% (34/109) were in the short-term, 29% (32/109) in the medium-term, and 39% (43/109) in the long-term group. A recurrent seizure was experienced by 47% (16/34) of the patients in the short-term, 31% (10/32) in the medium-term, and 44% (19/43) in the long-term group. Seizure recurrence risk was similar between patients in the short-term group as compared to the medium-term (cause-specific adjusted hazard ratio [aHR] = 0.65 [95%CI = 0.29-1.46]) and long-term group (cause-specific aHR = 1.04 [95%CI = 0.52-2.09]). CONCLUSIONS: Seizure recurrence risk is relatively similar between patients with short-term, medium-term, and long-term seizure freedom after completion of antitumour treatment.

Effectiveness of Antiseizure Medication Triple Therapy in Patients With Glioma With Refractory Epilepsy: An Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Approximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate whether levetiracetam combined with valproic acid and clobazam (LEV + VPA + CLB), a frequently prescribed triple therapy, has favorable effectiveness compared with other triple therapy combinations in patients with glioma. METHODS: This was a multicenter retrospective observational cohort study. The primary outcome was the cumulative incidence of time to treatment failure for any reason, from the start of ASM triple therapy treatment. The secondary outcomes included cumulative incidences of the following: (1) time to treatment failure due to uncontrolled seizures; (2) time to treatment failure due to adverse effects; and (3) time to recurrent seizures. Patients were followed up for a maximum duration of 36 months. RESULTS: Of 1,435 patients in the original cohort, 90 patients received ASM triple therapy after second-line ASM treatment failure due to uncontrolled seizures. LEV + VPA + CLB was prescribed to 48% (43/90) and other ASM triple therapy to 52% (47/90) of patients. The cumulative incidence of treatment failure for any reason of LEV + VPA + CLB did not statistically significantly differ from that of other ASM triple therapy combinations (12 months: 47% [95% CI 31%-62%] vs 42% [95% CI 27%-56%], p = 0.892). No statistically significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95% CI 4%-25%] vs 18% [95% CI 8%-30%], p = 0.445), adverse effects (12 months: 22% [95% CI 11%-36%] vs 15% [95% CI 7%-27%], p = 0.446), or recurrent seizures (1 month: 65% [95% CI 48%-78%] vs 63% [95% CI 47%-75%], p = 0.911) were found. DISCUSSION: LEV + VPA + CLB might show equivalent effectiveness compared with other ASM triple therapy combinations in patients with glioma. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with glioma with refractory epilepsy on triple therapy ASMs, LEV + VPA + CLB demonstrated similar effectiveness and tolerability compared with other ASM triple therapy combinations.

Study protocol of the GLOW study: maximising treatment options for recurrent glioblastoma patients by whole genome sequencing-based diagnostics-a prospective multicenter cohort study.

BACKGROUND: Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. METHODS: The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. DISCUSSION: The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186064.

Advance care planning (ACP) in glioblastoma patients: Evaluation of a disease-specific ACP program and impact on outcomes.

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 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.

Effectiveness of Antiseizure Medication Duotherapies in Patients With Glioma: A Multicenter Observational Cohort Study.

BACKGROUND AND OBJECTIVES: About 30% of patients with glioma need an add-on antiseizure medication (ASM) due to uncontrolled seizures on ASM monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV + VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in patients with glioma. METHODS: In this multicenter retrospective observational cohort study, treatment failure (i.e., replacement by, addition of, or withdrawal of an ASM) for any reason was the primary outcome. Secondary outcomes included (1) treatment failure due to uncontrolled seizures and (2) treatment failure due to adverse effects. Time to treatment failure was estimated from the moment of ASM duotherapy initiation. Multivariable cause-specific Cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months. RESULTS: A total of 1,435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received ASM duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV + VPA was prescribed in 66% (236/355) and other ASM duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy vs LEV + VPA had a higher risk of treatment failure for any reason (cause-specific adjusted hazard ratio [aHR] 1.50 [95% CI 1.07-2.12], p = 0.020), due to uncontrolled seizures (cause-specific aHR 1.73 [95% CI 1.10-2.73], p = 0.018), but not due to adverse effects (cause-specific aHR 0.88 [95% CI 0.47-1.67], p = 0.703). DISCUSSION: This observational cohort study suggests that LEV + VPA has better efficacy than other ASM combinations. Similar toxicities were experienced in the 2 groups. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with glioma with uncontrolled seizures on ASM monotherapy, LEV + VPA has better efficacy than other ASM combinations.

The impact of different volumetric thresholds to determine progressive disease in patients with recurrent glioblastoma treated with bevacizumab.

Background: The optimal volumetric threshold for determining progressive disease (PD) in recurrent glioblastoma is yet to be determined. We investigated a range of thresholds in association with overall survival (OS). Methods: First recurrent glioblastoma patients treated with bevacizumab and/or lomustine were included from the phase II BELOB and phase III EORTC26101 trials. Enhancing and nonenhancing tumor volumes were measured at baseline, first (6 weeks), and second (12 weeks) follow-up. Hazard ratios (HRs) for the appearance of new lesions and several thresholds for tumor volume increase were calculated using cox regression analysis. Results were corrected in a multivariate analysis for well-established prognostic factors. Results: At first and second follow-up, 138 and 94 patients respectively, were deemed eligible for analysis of enhancing volumes, while 89 patients were included in the analysis of nonenhancing volumes at first follow-up. New lesions were associated with a significantly worse OS (3.2 versus 11.2 months, HR = 7.03, P < .001). At first follow-up a threshold of enhancing volume increase of ≥20% provided the highest HR (5.55, p = .001. At second follow-up, any increase in enhancing volume (≥0%) provided the highest HR (9.00, p < .001). When measuring nonenhancing volume at first follow-up, only 6 additional patients were scored as PD with the highest HR of ≥25% increase in volume (HR=3.25, p = .008). Conclusion: Early appearing new lesions were associated with poor OS. Lowering the volumetric threshold for PD at both first and second follow-up improved survival prediction. However, the additional number of patients categorized as PD by lowering the threshold was very low. The per-RANO added change in nonenhancing volumes to the analyses was of limited value.

Is the EORTC QLQ-C30 emotional functioning scale appropriate as an initial screening measure to identify brain tumour patients who may possibly have a mood disorder?

BACKGROUND: Screening glioma patients regularly for possible mood disorders may facilitate early identification and referral of patients at risk. This study evaluated if the EORTC QLQ-C30 Emotional Functioning (EF) scale could be used as an initial screening measure to identify patients possibly having a mood disorder. METHODS: EORTC QLQ-C30 EF and Hospital Anxiety and Depression Scale (HADS) scores were collected as part of a study assessing the impact of timing of patient-reported outcome assessments on actual health-related quality of life outcomes (N = 99). Spearman correlations and Mann-Whitney U tests were used to determine the association between the EF and HADS (sub)scales. Receiver Operating Characteristic analyses were performed to determine optimal cut-off EF scores to identify patients possibly having a mood disorder (i.e. HADS subscale score ≥8 points). RESULTS: EF and HADS (sub)scales correlated moderately (HADS-A: r = -0.65; HADS-D: r = -0.52). Significant EF score differences were found between patients with HADS ≥8 versus <8 points (HADS-A: mean difference (MD) = 32 and HADS-D: MD = 23). The EF scale had excellent (HADS-A; AUC = 0.88) and borderline excellent (HADS-D; AUC = 0.78) distinguishing capabilities. A statistically optimal (EF score <80) and a most inclusive (sensitivity of 100%, corresponding to an EF score <97) EF cut-off score correctly identified 88.0% and 96.0% of patients with a possible mood disorder, respectively. CONCLUSION: EORTC QLQ-C30 EF scale seems to be an appropriate screening measure to identify glioma patients possibly having a mood disorder in need of further assessment.

Identification of characteristics that determine behavioral and personality changes in adult glioma patients.

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 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.

First-line antiepileptic drug treatment in glioma patients with epilepsy: Levetiracetam vs valproic acid.

OBJECTIVE: This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first-line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy. METHODS: In this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow-up was 36 months. RESULTS: In total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%-38%] vs 50% [95% CI 45%-55%]; P < .001). When looking at specific reasons of treatment failure, treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95% CI 12%-19%] vs 28% [95% CI 23%-32%]; P < 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95% CI 11%-18%] vs 15% [95% CI 11%-18%]; P = .636). SIGNIFICANCE: Our results suggest that levetiracetam may have favorable efficacy compared to valproic acid, whereas level of toxicity seems similar. Therefore, levetiracetam seems to be the preferred choice for first-line AED treatment in patients with glioma.

The Impact of the Timing of Health-Related Quality of Life Assessments on the Actual Results in Glioma Patients: A Randomized Prospective Study.

BACKGROUND: The aim of this study was to explore the impact of the timing of Health-Related Quality of Life (HRQoL) measurements in clinical care on the obtained HRQoL scores in glioma patients, and the association with feelings of anxiety or depression. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC)'s Quality of Life Questionnaires (QLQ-C30 and QLQ-BN20), and the Hospital Anxiety and Depression Scale (HADS) twice. All patients completed the first measurement on the day of the Magnetic Resonance Imaging (MRI) scan (t = 0), but the second measurement (t = 1) depended on randomization; Group 1 (n = 49) completed the questionnaires before and Group 2 (n = 51) after the consultation with the physician. RESULTS: median HRQoL scale scores on t0/t1 and change scores were comparable between the two groups. Between 8-58% of patients changed to a clinically relevant extent (i.e., ≥10 points) on the evaluated HRQoL scales in about one-week time, in both directions, with only 3% of patients remaining stable in all scales. Patients with a stable role functioning had a lower HADS anxiety change score. The HADS depression score was not associated with a change in HRQoL. CONCLUSIONS: Measuring HRQoL before or after the consultation did not impact HRQoL scores on a group level. However, most patients reported a clinically relevant difference in at least one HRQoL scale between the two time points. These findings highlight the importance of standardized moments of HRQoL assessments, or patient-reported outcomes in general, during treatment and follow-up in clinical trials.

Prediagnostic symptoms and signs of adult glioma: the patients' view.

BACKGROUND: Little is known about the symptoms glioma patients experience in the year before diagnosis, either or not resulting in health care usage. This study aimed to determine the incidence of symptoms glioma patients experienced in the year prior to diagnosis, and subsequent visits to a general practitioner (GP). METHODS: Glioma patients were asked to complete a 30-item study-specific questionnaire focusing on symptoms they experienced in the 12 months before diagnosis. For each indicated symptom, patients were asked whether they consulted the GP for this issue. RESULTS: Fifty-nine patients completed the questionnaires, 54 (93%) with input of a proxy. The median time since diagnosis was 4 months (range 1-12). The median number of symptoms experienced in the year before diagnosis was similar between gliomas with favourable and poor prognosis, i.e. 6 (range 0-24), as were the five most frequently mentioned problems: fatigue (n = 34, 58%), mental tiredness (n = 30, 51%), sleeping disorder (n = 24, 41%), headache (n = 23, 39%) and stress (n = 20, 34%). Twenty-six (44%) patients visited the GP with at least one issue. Patients who did consult their GP reported significantly more often muscle weakness (11 vs 3, p = 0.003) than patients who did not, which remained significant after correction for multiple testing, which was not the case for paralysis in hand/leg (10 vs 4), focussing (11 vs 6) or a change in awareness (9 vs 4). CONCLUSIONS: Glioma patients experience a range of non-specific problems in the year prior to diagnosis, but only patients who consult the GP report more often neurological problems.

Advance care planning in glioblastoma patients: development of a disease-specific ACP program.

BACKGROUND: It is unknown if the implementation of an advance care planning (ACP) program is feasible in daily clinical practice for glioblastoma patients. We aimed to develop an ACP program and assess the preferred content, the best time to introduce such a program in the disease trajectory, and possible barriers and facilitators for participation and implementation. METHODS: A focus group with health care professionals (HCPs) and individual semi-structured interviews with patients and proxies (of both living and deceased patients) were conducted. RESULTS: All predefined topics were considered relevant by participants, including the current situation, worries/fears, (supportive) treatment options, and preferred place of care/death. Although HCPs and proxies of deceased patients indicated that the program should be implemented relatively early in the disease trajectory, patient-proxy dyads were more ambiguous. Several patient-proxy dyads indicated that the program should be initiated later in the disease trajectory. If introduced early, topics about the end of life should be postponed. A frequently mentioned barrier for participation was that the program would be too confronting, while a facilitator was adequate access to information. CONCLUSION: This study resulted in an ACP program specifically for glioblastoma patients. Although participants agreed on the program content, the optimal timing of introducing such a program was a matter of debate. Our solution is to offer the program shortly after diagnosis but let patients and proxies decide which topics they want to discuss and when. The impact of the program on several patient- and care-related outcomes will be evaluated in the next step.

Internet-based guided self-help for glioma patients with depressive symptoms: a randomized controlled trial.

Depressive symptoms are common in glioma patients, and can negatively affect health-related quality of life (HRQOL). We performed a nation-wide randomized controlled trial to evaluate the effects of an online guided self-help intervention for depressive symptoms in adult glioma patients. Glioma patients with depressive symptoms were randomized to a 5-week online course based on problem-solving therapy, or a waiting list control group. After having received the intervention, the glioma patient groups combined were compared with patients with cancer outside the central nervous system (non-CNS cancer controls), who also received the intervention. Sample size calculations yielded 63 participants to be recruited per arm. The primary outcome [depressive symptoms (CES-D)] and secondary outcomes [fatigue (Checklist Individual Strength (CIS)) and HRQOL (Short Form-36)], were assessed online at baseline, post-intervention, and 3 and 12 months follow-up. In total, 89 glioma patients (intervention N = 45; waiting list N = 44) and 26 non-CNS cancer controls were included, of whom 35 and 54% completed the intervention, respectively. Recruitment could not be extended beyond 3.5 years due to funding. On depression, no statistically significant differences between the groups were found. Fatigue decreased post-treatment in the glioma intervention group compared with the waiting list group (p = 0.054, d = 0.306). At 12 months, the physical component summary (HRQOL) remained stable in glioma patients, while scores improved in non-CNS cancer controls (p = 0.035, d = 0.883). In this underpowered study, no evidence for the effectiveness of online guided self-help for depression or HRQOL in glioma patients was found, but it may improve fatigue. Trial registration Netherlands Trial Register NTR3223.

Visual inspection of MR relative cerebral blood volume maps has limited value for distinguishing progression from pseudoprogression in glioblastoma multiforme patients.

AIM: We examined whether visual interpretation of relative cerebral blood volume (rCBV) color maps made with dynamic susceptibility-weighted perfusion MRI can reliably distinguish progressive disease (PD) from pseudoprogression (PsPD) in glioblastoma patients during treatment with temozolomide chemoradiation. MATERIALS & METHODS: Magnetic resonance (MR) perfusion-weighted images were evaluated based on visual inspection of rCBV maps. Sensitivity and specificity were calculated to assess if rCBV can reliably differentiate between PD and PsPD, during standard chemoradiation therapy. RESULTS: Evaluation of dynamic susceptibility-weighted contrast-enhanced perfusion MRI by visual interpretation of rCBV maps did not differentiate PD from PsPD (sensitivity = 72%; specificity = 23%). Furthermore, the interpretation of the rCBV maps had no prognostic value regarding survival. CONCLUSION: Qualitative rCBV-based dynamic susceptibility-weighted contrast-enhanced perfusion MRI does not reliably differentiate PD from PsPD, and is not prognostic for survival in glioblastoma multiforme patients during treatment with temozolomide chemoradiation.

Comparison of 2D (RANO) and volumetric methods for assessment of recurrent glioblastoma treated with bevacizumab-a report from the BELOB trial.

Background: The current method for assessing progressive disease (PD) in glioblastoma is according to the Response Assessment in Neuro-Oncology (RANO) criteria. Bevacizumab-treated patients may show pseudo-response on postcontrast T1-weighted (T1w) MRI, and a more infiltrative non-enhancing growth pattern on T2w/fluid attenuated inversion recovery (FLAIR) images. We investigated whether the RANO criteria remain the method of choice for assessing bevacizumab-treated recurrent glioblastoma when compared with various volumetric methods. Methods: Patients with assessable MRI data from the BELOB trial (n = 148) were included. Patients were treated with bevacizumab, lomustine, or both. At first and second radiological follow-up (6 and 12 wk), PD was determined using the 2D RANO criteria and various volumetric methods based on enhancing tumor only and enhancing plus non-enhancing tumor. Differences in overall survival (OS) between PD and non-PD patients were assessed with the log-rank test and a Cox model. Hazard ratios (HRs) and their 95% CIs were determined. Results: For all patients together, all methods (except subtraction of non-enhancing from enhancing volume at first follow-up) showed significant differences in OS between PD and non-PD patients (P < .001). The largest risk increase for death in case of PD at both first and second follow-up was found with the RANO criteria: HR = 2.81 (95% CI, 1.92-4.10) and HR = 2.80 (95% CI, 1.75-4.49), respectively. In the bevacizumab-treated patients, all methods assessed showed significant differences in OS between PD and non-PD patients. There were no significant differences between methods. Conclusions: In the first 12 weeks, volumetric methods did not provide significant improvement over the RANO criteria as a posttreatment prognostic marker.

Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide.

We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were a ≥50 % seizure reduction and MRI response 6, 12 and 18 months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95 % CI 0.19-0.73; p = 0.004) and OS (HR 0.39; 95 % CI 0.18-0.85; p = 0.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95 % CI 62.0-112.9) than patients without a response (median 34.4mo; 95 % CI 26.1-42.6; p = 0.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.

Prevalence of changes in personality and behavior in adult glioma patients: a systematic review.

BACKGROUND: Gliomas are rare, with a dismal outcome and an obvious impact on quality of life, because of neurological, physical and cognitive problems, as well as personality and behavioral changes. These latter changes may affect the lives of both patients and their relatives in a profound way, but it is unclear how often this occurs and to what extent. METHODS: We performed a systematic review to determine the prevalence of changes in personality and behavior in glioma patients. Searches were conducted in PubMed/Medline, PsycINFO, Cochrane, CINAHL and Embase. Based on predetermined in- and exclusion criteria, papers were screened for eligibility. Information on the topics of interest were extracted from the full-text papers. RESULTS: The search yielded 9895 papers, of which 18 were found to be eligible; 9 qualitative and 9 quantitative studies. The reported prevalence rates of changes in personality and/or behavior varied from 8%-67% in glioma patients, and was 100% in a case series with bilateral gliomas. Moreover, these changes were associated with distress and a lower quality of life of patients as well as informal caregivers. Methods of measurement of personality and behavioral changes differed considerably, as did the description of these changes. CONCLUSION: To determine the true prevalence of changes in behavior and personality, present but poorly labeled in the reported studies, prospective studies are needed using proper definitions of personality and behavioral changes and validated measurement tools. Ultimately, these findings may result in improved supportive care of both patients and caregivers, during the disease trajectory.

The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial.

BACKGROUND: The BELOB study, a randomised controlled phase 2 trial comparing lomustine, bevacizumab and combined lomustine and bevacizumab in patients with recurrent glioblastoma, showed that the 9-month overall survival rate was most promising in the combination arm. Here we report the health-related quality of life (HRQoL) results, a secondary trial end-point. METHODS: HRQoL was measured at baseline and every 6weeks until progression using the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20). HRQoL was assessed over time for five preselected scales (global health (GH), physical (PF) and social functioning (SF), motor dysfunction (MD) and communication deficit (CD)). Moreover, mean changes in HRQoL from baseline until progression were determined. RESULTS: 138/148 patients with at least a baseline HRQoL assessment were analysed. Over time, HRQoL remained relatively stable in all treatment arms for all five scales, at least during the first three treatment cycles. More than half (54-61%) of the patients showed stable (<10 point change) or improved (⩾10 point change) HRQoL during their progression-free time, except for SF (43%), irrespective of treatment arm. Deterioration of mean HRQoL was most profound at disease progression for all scales except SF, which deteriorated earlier in disease course. Compared to baseline, 40% of patients had clinically relevant (⩾10 points) worse GH, PF and SF, while 44% and 31% had increased MD and CD at disease progression, irrespective of treatment arm. CONCLUSIONS: Bevacizumab, whether or not in combination with lomustine, did not negatively affect HRQoL in patients treated for recurrent glioblastoma in this randomised study.

Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide.

BACKGROUND: Seizures are a common symptom in patients with low-grade glioma (LGG), negatively influencing quality of life, if uncontrolled. Besides antiepileptic drugs, antitumour treatment might contribute to a reduction in seizure frequency. The aim of this study was to determine the effect of temozolomide (TMZ) chemotherapy on seizure frequency, to identify factors associated with post-treatment seizure reduction and to analyse the prognostic value of seizure reduction for survival. METHODS: We retrospectively reviewed adult patients with supratentorial LGG and epilepsy who received chemotherapy with TMZ as initial treatment or for progressive disease in two hospitals (VUmc Amsterdam; MCH The Hague) between 2002 and 2012. RESULTS: We identified 104 patients with LGG with epilepsy who had received TMZ. Uncontrolled epilepsy in the 3 months preceding chemotherapy was present in 66 of 104 (63.5%) patients. A ≥ 50% reduction in seizure frequency after 6 months occurred in 29 of 66 (43.9%) patients. Focal symptoms at presentation (OR 6.55; 95% CI 1.45 to 32.77; p = 0.015) appeared to be positively associated with seizure reduction. Seizure reduction was an independent prognostic factor for progression-free survival (HR 0.32; 95% CI 0.15 to 0.66; p = 0.002) and overall survival (HR 0.33; 95% CI 0.14 to 0.79; p = 0.013), along with a histological diagnosis of oligodendroglioma (HR 0.38; 95% CI 0.17 to 0.86; p = 0.021). Objective responses on MRI were similar for patients with and without seizure reduction. CONCLUSIONS: TMZ may contribute to an important reduction in seizure frequency in patients with LGG. Seizure reduction following TMZ treatment has prognostic significance and may serve as an important clinical outcome measure in patients with LGG.