Association between tumor location and neurocognitive functioning using tumor localization maps.

INTRODUCTION: Patients with diffuse glioma often experience neurocognitive impairment already prior to surgery. Pertinent information on whether damage to a specific brain region due to tumor activity results in neurocognitive impairment or not, is relevant in clinical decision-making, and at the same time renders unique information on brain lesion location and functioning relationships. To examine the impact of tumor location on preoperative neurocognitive functioning (NCF), we performed MRI based lesion-symptom mapping. METHODS: Seventy-two patients (mean age 40 years) with a radiologically suspected glioma were recruited preoperatively. For each of the six cognitive domains tested, we used tumor localization maps and voxel-based lesion-symptom mapping analyses to identify cortical and subcortical regions associated with NCF impairment. RESULTS: Compared to healthy controls, preoperative NCF was significantly impaired in all cognitive domains. Most frequently affected were attention (30% of patients) and working memory (20% of patients). Deficits in attention were significantly associated with regions in the left frontal and parietal cortex, including the precentral and parietal-opercular cortex, and in left-sided subcortical fiber tracts, including the arcuate fasciculus and corticospinal tract. Surprisingly, no regions could be related to working memory capacity. For the other neurocognitive domains, impairments were mainly associated with regions in the left hemisphere. CONCLUSIONS: Prior to treatment, patients with diffuse glioma in the left hemisphere run the highest risk to have NCF deficits. Identification of a left frontoparietal network involved in NCF not only may optimize surgical procedures but may also be integrated in counseling and cognitive rehabilitation for these patients.

Cognitive functioning and health-related quality of life in patients with newly diagnosed primary CNS lymphoma: a systematic review.

Incidence of primary CNS lymphoma (PCNSL) is increasing, while prognosis is improving as treatments advance. However, declined cognitive functioning remains a major challenge in the treatment of PCNSL. This cognitive decline, in conjunction with other symptoms caused by the disease or its treatment, or both, can compromise health-related quality of life (HRQOL). The aim of this Review was to give a comprehensive overview on cognitive functioning and HRQOL for patients with PCNSL, including an evaluation of patient-related and treatment-related factors that can influence cognitive functioning and HRQOL. We reviewed the literature for studies on cognitive functioning and HRQOL in newly diagnosed adult patients with PCNSL using MEDLINE/PubMed, Embase, Web of Science, Scopus, Cochrane, PsycINFO, CINAHL EBSCO, and Google Scholar, up to Jan 4, 2018. Articles were selected using predetermined inclusion and exclusion criteria; 42 articles were eligible for inclusion. Findings show that the tumour itself has a great effect on cognitive functioning and HRQOL. Initially, induction chemotherapy results in improvement of cognition and HRQOL in most patients. In the long-term, the addition of whole-brain radiotherapy has a negative effect on cognitive functioning, but the magnitude of this effect is not always clinically relevant. HRQOL scores were worse compared with controls, and worse after combined chemotherapy and radiotherapy when compared with chemotherapy only, particularly in the long term. Therefore, combined chemotherapy and radiotherapy seems to have a negative effect on HRQOL and cognition in patients with PCNSL. Although prolonged progression-free survival is achieved with combined treatment, information on its effect on cognition and HRQOL should be included in clinical decision-making.

Linking late cognitive outcome with glioma surgery location using resection cavity maps.

Patients with a diffuse glioma may experience cognitive decline or improvement upon resective surgery. To examine the impact of glioma location, cognitive alteration after glioma surgery was quantified and related to voxel-based resection probability maps. A total of 59 consecutive patients (range 18-67 years of age) who had resective surgery between 2006 and 2011 for a supratentorial nonenhancing diffuse glioma (grade I-III, WHO 2007) were included in this observational cohort study. Standardized neuropsychological examination and MRI were obtained before and after surgery. Intraoperative stimulation mapping guided resections towards neurological functions (language, sensorimotor function, and visual fields). Maps of resected regions were constructed in standard space. These resection cavity maps were compared between patients with and without new cognitive deficits (z-score difference >1.5 SD between baseline and one year after resection), using a voxel-wise randomization test and calculation of false discovery rates. Brain regions significantly associated with cognitive decline were classified in standard cortical and subcortical anatomy. Cognitive improvement in any domain occurred in 10 (17%) patients, cognitive decline in any domain in 25 (42%), and decline in more than one domain in 10 (17%). The most frequently affected subdomains were attention in 10 (17%) patients and information processing speed in 9 (15%). Resection regions associated with decline in more than one domain were predominantly located in the right hemisphere. For attention decline, no specific region could be identified. For decline in information speed, several regions were found, including the frontal pole and the corpus callosum. Cognitive decline after resective surgery of diffuse glioma is prevalent, in particular, in patients with a tumor located in the right hemisphere without cognitive function mapping.

Individual changes in neurocognitive functioning and health-related quality of life in patients with brain oligometastases treated with stereotactic radiotherapy.

BACKGROUND: Recently, it has been shown that at group level, patients with limited brain metastases treated with stereotactic radiotherapy (SRT) maintain their pre-treatment levels of neurocognitive functioning (NCF) and health-related quality of life (HRQoL). The aim of this study was to evaluate NCF and HRQoL changes over time at the individual patient level. METHODS: NCF (seven domains assessed with a standardized test battery) and HRQoL (eight predetermined scales assessed with the EORTC QLQ-C30 and BN20 questionnaires) were measured prior to SRT and at 3 and/or 6 months follow-up. Changes in NCF and HRQoL were evaluated at (1) a domain/scale level and (2) patient level. RESULTS: A total of 55 patients were examined, of which the majority showed stable NCF 3 months after SRT, on both the domain level (78-100% of patients) and patient level (67% of patients). This was different for HRQoL, where deterioration in the different scales was observed in 12-61% of patients, stable scores in 20-71%, and improvement in 16-40%, 3 months after SRT. At patient level, most patients (64%) showed both improvement and deterioration in different HRQoL scales. Results were similar between 3 and 6 months after SRT. CONCLUSION: In line with results at group level, most brain oligometastases patients with ≥ 6 months follow-up and treated with SRT maintained their pre-treatment level of NCF during this period. By contrast, changes in HRQoL scores differed considerably at domain and patient level, despite stable HRQoL scores at group level.

Health-related quality of life and cognitive functioning in long-term anaplastic oligodendroglioma and oligoastrocytoma survivors.

Overall survival of patients with anaplastic oligodendroglial tumors has been improved due to the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy to radiotherapy (RT), especially in 1p/19q-codeleted tumors. With improved survival, quality of survival becomes pivotal. We evaluated cognitive functioning and health-related quality of life (HRQOL) in a cohort of long-term anaplastic oligodendroglioma survivors. Thirty-two out of 37 long-term survivors included in European Organisation for Research and Treatment of Cancer (EORTC) study 26951 in the Netherlands and France participated. Cognition was assessed using neuropsychological tests for 6 domains, and HRQOL with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) and Brain Cancer Module (EORTC QLQ-BN20). Fatigue and mood were evaluated. Results were compared to healthy controls and to patients' own HRQOL 2.5 years following initial treatment. At the time of assessment, median survival for the patients was 147 months, 27 were still progression-free since initial treatment. Of progression-free patients, 26% were not, and 30% were severely cognitively impaired; 41% were employed and 81% could live independently. Patients' HRQOL was worse compared to controls, but similar to 2.5 years after initial treatment. Initial treatment (RT versus RT + PCV) was not correlated with cognition or HRQOL. In conclusion, cognitive functioning in long-term anaplastic oligodendroglioma survivors is variable. However, most patients function independently. In progression-free patients, HRQOL is relatively stable during the disease course. In this small sample, no effect of the addition of PCV on cognition or HRQOL was identified.

Tumour and surgery effects on cognitive functioning in high-grade glioma patients.

BACKGROUND: Many high-grade glioma (HGG) patients have cognitive impairments, which impact daily functioning. Cognitive impairments can be caused by tumour-, treatment-, and patient-related factors. The effect of the tumour and of surgical resection on cognition is, however, not well known. We investigated tumour and surgical effects on cognitive functioning in patients with HGG. METHODS: At baseline, preceding surgery, 62 patients with HGG underwent neuropsychological testing concerning seven cognitive domains: verbal and working memory, attention, executive functioning, psychomotor function, information processing speed, and visuoconstructive abilities. Thirty-nine patients were included in follow-up testing after surgery, but before subsequent treatment. Tumour size and site, use of anti-epileptic drugs and corticosteroids, and extent of resection were recorded. RESULTS: Compared to healthy controls, cognitive functioning of patients was significantly impaired in all domains. Prior to surgery 79 % (49 of 62) of patients had cognitive impairment in at least one domain. At median follow-up of 5 weeks after surgery, 59 % (23 of 39) of patients were cognitively impaired in at least one domain. At follow-up, 49 % showed improvement, while 23 % declined. Left hemisphere tumour localization was associated with worse verbal memory (P=0.004), and larger tumours in this hemisphere with poorer executive functioning (P < 0.001). Changes in cognitive performance at follow-up relative to baseline were not related to tumour characteristics or extent of resection. CONCLUSIONS: Tumour-related cognitive deficits are present in a majority of HGG patients preceding surgery. Surgery does not result in cognitive deterioration in the short term in most patients.

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.

Neurocognitive functioning and radiologic changes in primary CNS lymphoma patients: results from the HOVON 105/ALLG NHL 24 randomized controlled trial.

BACKGROUND: To analyze the effect of treatment on neurocognitive functioning and the association of neurocognition with radiological abnormalities in primary central nervous system lymphoma (PCNSL). METHODS: One hundred and ninety-nine patients from a phase III trial (HOVON 105/ALLG NHL 24), randomized to standard chemotherapy with or without rituximab, followed in patients ≤60 years old by 30-Gy whole-brain radiotherapy (WBRT), were asked to participate in a neuropsychological evaluation before and during treatment, and up to 2 years posttreatment. Scores were transformed into a standardized z-score; clinically relevant changes were defined as a change in z-score of ≥1 SD. The effect of WBRT was analyzed in irradiated patients. All MRIs were centrally assessed for white matter abnormalities and cerebral atrophy, and their relation with neurocognitive scores over time in each domain was calculated. RESULTS: 125/199 patients consented to neurocognitive evaluation. Statistically significant improvements in neurocognition were seen in all domains. A clinically relevant improvement was seen only in the motor speed domain, without differences between the arms. In the follow-up of irradiated patients (n = 43), no change was observed in any domain score, compared to after WBRT. Small but significant inverse correlations were found between neurocognitive scores over time and changes in white matter abnormalities (regression coefficients: -0.048 to -0.347) and cerebral atrophy (-0.212 to -1.774). CONCLUSIONS: Addition of rituximab to standard treatment in PCNSL patients did not impact neurocognitive functioning up to 2 years posttreatment, nor did treatment with 30-Gy WBRT in patients ≤60 years old. Increased white matter abnormalities and brain atrophy showed weak associations with neurocognition.

The level of reporting of neurocognitive outcomes in randomised controlled trials of brain tumour patients: A systematic review.

BACKGROUND: Neurocognitive impairment is frequently present in brain tumour patients and is therefore considered an important outcome in brain tumour research. To use neurocognitive outcomes (NCO) in clinical decision-making, neurocognitive evidence should be of sufficiently high quality. We aimed to investigate the level of neurocognitive functioning reporting in randomised controlled trials (RCTs) in brain tumour patients. METHODS: We conducted a systematic literature search in several databases up to August 2017. Of the selected relevant RCTs, the following data were retrieved: basic trial demographics and NCO characteristics, quality of NCO reporting and risk of bias. We also analysed studies that should impact clinical decision-making based on their quality of reporting. RESULTS: We identified 65 RCTs, of which NCO was the primary end-point in 14 (22%). Important methodological limitations were related to the documentation of statistical approaches for dealing with missing data and to discussing limitations and generalisability issues uniquely related to the NCO components. Risk of bias was high regarding blinding of personnel and incomplete outcome data. Twenty RCTs (31%), eight with NCO as primary end-point and 12 as secondary end-point, satisfied a sufficient number of criteria to be classified as 'high-quality' NCO evidence. Most of these studies did contribute to clinical decision-making. CONCLUSION: Investigators involved in brain tumour research should give attention to methodological challenges related to NCO reporting as identified in this review, as 'high-quality' reporting of NCO evidence can be of value in clinical decision-making.

The EORTC CAT Core-The computer adaptive version of the EORTC QLQ-C30 questionnaire.

BACKGROUND: To optimise measurement precision, relevance to patients and flexibility, patient-reported outcome measures (PROMs) should ideally be adapted to the individual patient/study while retaining direct comparability of scores across patients/studies. This is achievable using item banks and computerised adaptive tests (CATs). The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) is one of the most widely used PROMs in cancer research and clinical practice. Here we provide an overview of the research program to develop CAT versions of the QLQ-C30's 14 functional and symptom domains. METHODS: The EORTC Quality of Life Group's strategy for developing CAT item banks consists of: literature search to identify potential candidate items; formulation of new items compatible with the QLQ-C30 item style; expert evaluations and patient interviews; field-testing and psychometric analyses, including factor analysis, item response theory calibration and simulation of measurement properties. In addition, software for setting up, running and scoring CAT has been developed. RESULTS: Across eight rounds of data collections, 9782 patients were recruited from 12 countries for the field-testing. The four phases of development resulted in a total of 260 unique items across the 14 domains. Each item bank consists of 7-34 items. Psychometric evaluations indicated higher measurement precision and increased statistical power of the CAT measures compared to the QLQ-C30 scales. Using CAT, sample size requirements may be reduced by approximately 20-35% on average without loss of power. CONCLUSIONS: The EORTC CAT Core represents a more precise, powerful and flexible measurement system than the QLQ-C30. It is currently being validated in a large independent, international sample of cancer patients.

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.

Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study.

BACKGROUND: Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect on neurocognitive functioning and health-related quality of life (HRQoL) than whole-brain radiotherapy. To evaluate the impact of brain metastases and SRT on neurocognitive functioning and HRQoL, we performed a prospective study. METHODS: Neurocognitive functioning and HRQoL of 97 patients with brain metastases were measured before SRT and 1, 3, and 6 months after SRT. Seven cognitive domains were assessed. HRQoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and BN20 questionnaires. Neurocognitive functioning and HRQoL over time were analyzed with linear mixed models and stratified for baseline Karnofsky performance status (KPS), total metastatic volume, and systemic disease. RESULTS: Median overall survival of patients was 7.7 months. Before SRT, neurocognitive domain and HRQoL scores were lower in patients than in healthy controls. At group level, patients worsened in physical functioning and fatigue at 6 months, while other outcome parameters of HRQoL and cognition remained stable. KPS < 90 and tumor volume >12.6 cm(3) were both associated with worse information processing speed and lower HRQoL scores over 6 months time. Intracranial tumor progression was associated with worsening of executive functioning and motor function. CONCLUSIONS: Prior to SRT, neurocognitive functioning and HRQoL are moderately impaired in patients with brain metastases. Lower baseline KPS and larger tumor volume are associated with worse functioning. Over time, SRT does not have an additional detrimental effect on neurocognitive functioning and HRQoL, suggesting that SRT may be preferred over whole-brain radiotherapy.