Verbal fluency as a quick and simple tool to help in deciding when to refer patients with a possible brain tumour.

BACKGROUND: Patients with brain tumours often present with non-specific symptoms. Correctly identifying who to prioritise for urgent brain imaging is challenging. Brain tumours are amongst the commonest cancers diagnosed as an emergency presentation. A verbal fluency task (VFT) is a rapid triage test affected by disorders of executive function, language and processing speed. We tested whether a VFT could support identification of patients with a brain tumour. METHODS: This proof-of-concept study examined whether a VFT can help differentiate patients with a brain tumour from those with similar symptoms (i.e. headache) without a brain tumour. Two patient populations were recruited, (a) patients with known brain tumour, and (b) patients with headache referred for Direct-Access Computed-Tomography (DACT) from primary care with a suspicion of a brain tumour. Semantic and phonemic verbal fluency data were collected prospectively. RESULTS: 180 brain tumour patients and 90 DACT patients were recruited. Semantic verbal fluency score was significantly worse for patients with a brain tumour than those without (P < 0.001), whether comparing patients with headache, or patients without headache. Phonemic fluency showed a similar but weaker difference. Raw and incidence-weighted positive and negative predictive values were calculated. CONCLUSION: We have demonstrated the potential role of adding semantic VFT score performance into clinical decision making to support triage of patients for urgent brain imaging. A relatively small improvement in the true positive rate in patients referred for DACT has the potential to increase the timeliness and efficiency of diagnosis and improve patient outcomes.

Development of an EORTC questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumours: phase I-III.

PURPOSE: Being able to function independently in society is an important aspect of quality of life. This ability goes beyond self-care, requires higher order cognitive functioning, and is typically measured with instrumental activities of daily living (IADL) questionnaires. Cognitive deficits are frequently observed in brain tumour patients, however, IADL is almost never assessed because no valid and reliable IADL measure is available for this patient group. Therefore, this measure is currently being developed. METHODS: This international multicentre study followed European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group module development guidelines. Three out of four phases are completed: phases (I) generation of items, (II) construction of the item list, and (III) pre-testing. This paper reports the item selection procedures and preliminary psychometric properties of the questionnaire. Brain tumour patients (gliomas and brain metastases), their informal caregivers, and health care professionals (HCPs) were included. RESULTS: Phase I (n = 44 patient-proxy dyads and 26 HCPs) generated 59 relevant and important activities. In phase II, the activities were converted into items. In phase III (n = 85 dyads), the 59 items were pre-tested. Item selection procedures resulted in 32 items. Exploratory factor analysis revealed a preliminary dimensional structure consisting of five scales with acceptable to excellent internal consistency (α = 0.73-0.94) and two single items. For three scales, patients with cognitive impairments had significantly more IADL problems than patients without impairments. CONCLUSION: A phase IV validation study is needed to confirm the psychometric properties of the EORTC IADL-BN32 questionnaire in a larger international sample.

Economic evaluation of GPs' direct access to computed tomography for identification of brain tumours.

BACKGROUND: When GPs suspect a brain tumour, a referral for specialist assessment and subsequent brain imaging is generally the first option. NICE has recommended that GPs have rapid direct access to brain imaging for adults with progressive sub-acute loss of central nervous function; however, no studies have evaluated the cost-effectiveness. METHODS: We developed a cost-effectiveness model based on data from one region of the UK with direct access computed tomography (DACT), routine data from GP records and the literature, to explore whether unrestricted DACT for patients with suspected brain tumour might be more cost-effective than criteria-based DACT or no DACT. RESULTS: Although criteria-based DACT allows some patients without brain tumour to avoid imaging, our model suggests this may increase costs of diagnosis due to non-specific risk criteria and high costs of diagnosing or 'ruling out' brain tumours by other pathways. For patients diagnosed with tumours, differences in outcomes between the three diagnostic strategies are small. CONCLUSIONS: Unrestricted DACT may reduce diagnostic costs; however, the evidence is not strong and further controlled studies are required. Criteria-based access to CT for GPs might reduce demand for DACT, but imperfect sensitivity and specificity of current risk stratification mean that it will not necessarily be cost-effective.

Effectiveness and tolerability of lacosamide as add-on therapy in patients with brain tumor-related epilepsy: Results from a prospective, noninterventional study in European clinical practice (VIBES).

OBJECTIVE: To evaluate the effectiveness and tolerability of lacosamide added to one or two antiepileptic drugs (AEDs) in the treatment of patients with brain tumor-related epilepsy (BTRE), and to evaluate patients' global impression of change and quality of life (QoL). METHODS: This was a prospective, multicenter, single-arm, noninterventional study with a 6-month observation period (EP0045; NCT02276053). Eligible patients (≥16 years old) had active BTRE secondary to low-grade glioma (World Health Organization grade 1 and 2) and were receiving treatment with one or two AEDs at baseline. Lacosamide was initiated by the treating physician in the course of routine clinical practice. Primary outcomes were 50% responders (≥50% reduction in focal seizure frequency from baseline) and Patient's Global Impression of Change (PGIC) at month 6. Secondary outcomes included seizure-free status and Clinical Global Impression of Change (CGIC) at month 6, change in QoL (5-Level EuroQol-5 Dimension Quality of Life Assessment) and symptom outcomes (MD Anderson Symptom Inventory-Brain Tumor) from baseline to month 6, and Kaplan-Meier estimated 6-month retention on lacosamide. Safety variables included adverse drug reactions (ADRs). RESULTS: Patients were recruited from 24 sites in Europe. Ninety-three patients received lacosamide (mean [standard deviation] age = 44.5 [14.7] years; 50 [53.8%] male; median baseline focal seizure frequency = five seizures/28 days [range = 1-280]), of whom 79 (84.9%) completed the study. At 6 months, 66 of 86 (76.7%) patients were 50% responders and 30 of 86 (34.9%) were seizure-free. Improvements on PGIC were reported by 49 of 76 (64.5%) patients. Based on CGIC, 52 of 81 (64.2%) patients improved. QoL and symptoms outcome measures remained stable. Kaplan-Meier estimated 6-month retention rate was 86.0% (N = 93). Fifteen (16.1%) patients reported ADRs; four (4.3%) had ADRs leading to discontinuation (N = 93). SIGNIFICANCE: Results of this prospective, noninterventional study suggest that add-on lacosamide is effective and generally well tolerated in patients with BTRE.

Treatment of newly diagnosed glioblastoma in the elderly: a network meta-analysis.

BACKGROUND: A glioblastoma is a fatal type of brain tumour for which the standard of care is maximum surgical resection followed by chemoradiotherapy, when possible. Age is an important consideration in this disease, as older age is associated with shorter survival and a higher risk of treatment-related toxicity. OBJECTIVES: To determine the most effective and best-tolerated approaches for the treatment of elderly people with newly diagnosed glioblastoma. To summarise current evidence for the incremental resource use, utilities, costs and cost-effectiveness associated with these approaches. SEARCH METHODS: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to 3 April 2019, and the NHS Economic Evaluation Database (EED) up to database closure. We handsearched clinical trial registries and selected neuro-oncology society conference proceedings from the past five years. SELECTION CRITERIA: Randomised trials (RCTs) of treatments for glioblastoma in elderly people. We defined 'elderly' as 70+ years but included studies defining 'elderly' as over 65+ years if so reported. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for study selection and data extraction. Where sufficient data were available, treatment options were compared in a network meta-analysis (NMA) using Stata software (version 15.1). For outcomes with insufficient data for NMA, pairwise meta-analysis were conducted in RevMan. The GRADE approach was used to grade the evidence. MAIN RESULTS: We included 12 RCTs involving approximately 1818 participants. Six were conducted exclusively among elderly people (either defined as 65 years or older or 70 years or older) with newly diagnosed glioblastoma, the other six reported data for an elderly subgroup among a broader age range of participants. Most participants were capable of self-care. Study quality was commonly undermined by lack of outcome assessor blinding and attrition. NMA was only possible for overall survival; other analyses were pair-wise meta-analyses or narrative syntheses. Seven trials contributed to the NMA for overall survival, with interventions including supportive care only (one trial arm); hypofractionated radiotherapy (RT40; four trial arms); standard radiotherapy (RT60; five trial arms); temozolomide (TMZ; three trial arms); chemoradiotherapy (CRT; three trial arms); bevacizumab with chemoradiotherapy (BEV_CRT; one trial arm); and bevacizumab with radiotherapy (BEV_RT). Compared with supportive care only, NMA evidence suggested that all treatments apart from BEV_RT prolonged survival to some extent. Overall survival High-certainty evidence shows that CRT prolongs overall survival (OS) compared with RT40 (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.56 to 0.80) and low-certainty evidence suggests that CRT may prolong overall survival compared with TMZ (TMZ versus CRT: HR 1.42, 95% CI 1.01 to 1.98). Low-certainty evidence also suggests that adding BEV to CRT may make little or no difference (BEV_CRT versus CRT: HR 0.83, 95% CrI 0.48 to 1.44). We could not compare the survival effects of CRT with different radiotherapy fractionation schedules (60 Gy/30 fractions and 40 Gy/15 fractions) due to a lack of data. When treatments were ranked according to their effects on OS, CRT ranked higher than TMZ, RT and supportive care only, with the latter ranked last. BEV plus RT was the only treatment for which there was no clear benefit in OS over supportive care only.   One trial comparing tumour treating fields (TTF) plus adjuvant chemotherapy (TTF_AC) with adjuvant chemotherapy alone could not be included in the NMA as participants were randomised after receiving concomitant chemoradiotherapy, not before. Findings from the trial suggest that the intervention probably improves overall survival in this selected patient population. We were unable to perform NMA for other outcomes due to insufficient data. Pairwise analyses were conducted for the following. Quality of life Moderate-certainty narrative evidence suggests that overall, there may be little difference in QoL between TMZ and RT, except for discomfort from communication deficits, which are probably more common with RT (1 study, 306 participants, P = 0.002). Data on QoL for other comparisons were sparse, partly due to high dropout rates, and the certainty of the evidence tended to be low or very low. Progression-free survival High-certainty evidence shows that CRT increases time to disease progression compared with RT40 (HR 0.50, 95% CI 0.41 to 0.61); moderate-certainty evidence suggests that RT60 probably increases time to disease progression compared with supportive care only (HR 0.28, 95% CI 0.17 to 0.46), and that BEV_RT probably increases time to disease progression compared with RT40 alone (HR 0.46, 95% CI 0.27 to 0.78). Evidence for other treatment comparisons was of low- or very low-certainty. Severe adverse events Moderate-certainty evidence suggests that TMZ probably increases the risk of grade 3+ thromboembolic events compared with RT60 (risk ratio (RR) 2.74, 95% CI 1.26 to 5.94; participants = 373; studies = 1) and also the risk of grade 3+ neutropenia, lymphopenia, and thrombocytopenia. Moderate-certainty evidence also suggests that CRT probably increases the risk of grade 3+ neutropenia, leucopenia and thrombocytopenia compared with hypofractionated RT alone. Adding BEV to CRT probably increases the risk of thromboembolism (RR 16.63, 95% CI 1.00 to 275.42; moderate-certainty evidence). Economic evidence There is a paucity of economic evidence regarding the management of newly diagnosed glioblastoma in the elderly. Only one economic evaluation on two short course radiotherapy regimen (25 Gy versus 40 Gy) was identified and its findings were considered unreliable. AUTHORS' CONCLUSIONS: For elderly people with glioblastoma who are self-caring, evidence suggests that CRT prolongs survival compared with RT and may prolong overall survival compared with TMZ alone. For those undergoing RT or TMZ therapy, there is probably little difference in QoL overall. Systemic anti-cancer treatments TMZ and BEV carry a higher risk of severe haematological and thromboembolic events and CRT is probably associated with a higher risk of these events. Current evidence provides little justification for using BEV in elderly patients outside a clinical trial setting. Whilst the novel TTF device appears promising, evidence on QoL and tolerability is needed in an elderly population. QoL and economic assessments of CRT versus TMZ and RT are needed. More high-quality economic evaluations are needed, in which a broader scope of costs (both direct and indirect) and outcomes should be included.

Interventions to reduce the time to diagnosis of brain tumours.

BACKGROUND: Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available. OBJECTIVES: To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions. SEARCH METHODS: For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014. SELECTION CRITERIA: We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non-randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author. MAIN RESULTS: We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic. AUTHORS' CONCLUSIONS: In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost-effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.

The Effects of Brain Tumours upon Medical Decision-Making Capacity.

PURPOSE OF REVIEW: Informed consent is the integral part of good medical practice in patients with brain tumours. Capacity to consent may be affected by the brain disorder or its treatment. We intend to draw upon the current neuro-oncology literature to discuss the influence intracranial tumours have upon patients' capacity to consent to treatment and research. RECENT FINDINGS: We performed a systematic review of studies of capacity to consent for treatment or research in patients with intracranial tumours. The search retrieved 1597 papers of which 8 were considered eligible for review. Although there are obvious inherent limitations to solely assessing cognition, most research consistently demonstrated increased risk of incapacity in brain tumour patients with cognitive impairment. Specific items in cognitive screening batteries, for example Semantic Verbal Fluency Test (SVFT), Hopkins Verbal Learning Test (HVLT-Recall), and Trail Making Test A/B (TMT), are simple, easily applied tests that may act as significant red flags to identify patients at increased risk of incapacity and who subsequently will require additional cognitive/psychiatric evaluation or more formal tests for capacity to consent for treatment or research.

Biopsy versus resection for high-grade glioma.

BACKGROUND: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 1, 2000 and updated in 2003, 2007 and 2010.People with a presumed high-grade glioma (HGG) identified by clinical evaluation and radiological investigation have two initial surgical options: biopsy or resection. In certain situations, such as severe raised intracranial pressure, surgical resection is clinically indicated. Where surgical resection is not feasible, biopsy is the only reasonable option. Most people fall somewhere between these extremes, and in such circumstances it is uncertain which procedure is the best surgical option for the patient. Opinion is divided regarding the relative risks and benefits of each procedure. OBJECTIVES: To estimate the clinical effectiveness of surgical resection compared to biopsy in people with a new presumptive diagnosis of HGG. SEARCH METHODS: We updated our searches of the following databases to 12 September 2018: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also handsearched the Journal of Neuro-Oncology and Neuro-Oncology from 2010 to 2018 (including all conference abstracts). SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving people of all ages with a presumed diagnosis of HGG based upon clinical and radiological investigation. Interventions included any form of biopsy or resection. Surgery was at the time of initial presentation and not for recurrence. DATA COLLECTION AND ANALYSIS: Two reviews authors independently assessed the search results for relevance and undertook critical appraisal according to prespecified guidelines. Outcome measures included survival, time to progression/progression-free survival, quality of life, symptom control, adverse events, and mortality. MAIN RESULTS: We identified a single RCT of biopsy versus resection in presumed HGG. No other articles met the inclusion criteria. Personal communication revealed that an RCT of biopsy versus resection in elderly people with HGG is underway. Further communication as part of this 2018 update revealed that the results of this study are due to be published in 2019. AUTHORS' CONCLUSIONS: There is no high-quality evidence on biopsy versus resection for HGG that can be used to guide management. The single included RCT was of inadequate methodology to reach reliable conclusions. Further large, multicentred RCTs are required to conclusively answer the question of whether biopsy or resection is the best initial surgical management for HGG.

Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma.

BACKGROUND: Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000. In this review we focus on gliomas with low aggressive potential in the short term, i.e. low-grade gliomas. Most people with low-grade gliomas are treated with surgery and may receive radiotherapy thereafter. However, there is concern about the possible long-term effects of radiotherapy, especially on neurocognitive functioning. OBJECTIVES: To evaluate the long-term neurocognitive and other side effects of radiotherapy (with or without chemotherapy) compared with no radiotherapy, or different types of radiotherapy, among people with glioma (where 'long-term' is defined as at least two years after diagnosis); and to write a brief economic commentary. SEARCH METHODS: We searched the following databases on 16 February 2018 and updated the search on 14 November 2018: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library; MEDLINE via Ovid; and Embase via Ovid. We also searched clinical trial registries and relevant conference proceedings from 2014 to 2018 to identify ongoing and unpublished studies. SELECTION CRITERIA: Randomised and non-randomised trials, and controlled before-and-after studies (CBAS). Participants were aged 16 years and older with cerebral glioma other than glioblastoma. We included studies where patients in at least one treatment arm received radiotherapy, with or without chemotherapy, and where neurocognitive outcomes were assessed two or more years after treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of findings using the GRADE approach. MAIN RESULTS: The review includes nine studies: seven studies were of low-grade glioma and two were of grade 3 glioma. Altogether 2406 participants were involved but there was high sample attrition and outcome data were available for a minority of people at final study assessments. In seven of the nine studies, participants were recruited to randomised controlled trials (RCTs) in which longer-term follow-up was undertaken in a subset of people that had survived without disease progression. There was moderate to high risk of bias in studies due to lack of blinding and high attrition, and in two observational studies there was high risk of selection bias. Paucity of data and risk of bias meant that evidence was of low to very low certainty. We were unable to combine results in meta-analysis due to diversity in interventions and outcomes.The studies examined the following five comparisons.Radiotherapy versus no adjuvant treatmentTwo observational studies contributed data. At the 12-year follow-up in one study, the risk of cognitive impairment (defined as cognitive disability deficits in at least five of 18 neuropsychological tests) was greater in the radiotherapy group (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.02 to 3.71; n = 65); at five to six years the difference between groups did not reach statistical significance (RR 1.38, 95% CI 0.92 to 2.06; n = 195). In the other study, one subject in the radiotherapy group had cognitive impairment (defined as significant deterioration in eight of 12 neuropsychological tests) at two years compared with none in the control group (very low certainty evidence).With regard to neurocognitive scores, in one study the radiotherapy group was reported to have had significantly worse mean scores on some tests compared with no radiotherapy; however, the raw data were only given for significant findings. In the second study, there were no clear differences in any of the various cognitive outcomes at two years (n = 31) and four years (n = 15) (very low certainty evidence).Radiotherapy versus chemotherapyOne RCT contributed data on cognitive impairment at up to three years with no clear difference between arms (RR 1.43, 95% CI 0.36 to 5.70, n = 117) (low-certainty evidence).High-dose radiotherapy versus low-dose radiotherapyOnly one of two studies reporting this comparison contributed data, and at two and five years there were no clear differences between high- and low-dose radiotherapy arms (very low certainty evidence).Conventional radiotherapy versus stereotactic conformal radiotherapyOne study involving younger people contributed limited data from the subgroup aged 16 to 25 years. The numbers of participants with neurocognitive impairment at five years after treatment were two out of 12 in the conventional arm versus none out of 11 in the stereotactic conformal radiotherapy arm (RR 4.62, 95% CI 0.25 to 86.72; n = 23; low-certainty evidence).Chemoradiotherapy versus radiotherapyTwo RCTs tested for cognitive impairment. One defined cognitive impairment as a decline of more than 3 points in MMSE score compared with baseline and reported data from 2-year (110 participants), 3-year (91 participants), and 5-year (57 participants) follow-up with no clear difference between the two arms at any time point. A second study did not report raw data but measured MMSE scores over five years in 126 participants at two years, 110 at three years, 69 at four years and 53 at five years. Authors concluded that there was no difference in MMSE scores between the two study arms (P = 0.4752) (low-certainty evidence).Two RCTs reported quality of life (QoL) outcomes for this comparison. One reported no differences in Brain-QoL scores between study arms over a 5-year follow-up period (P = 0.2767; no raw data were given and denominators were not stated). The other trial reported that the long-term results of health-related QoL showed no difference between the arms but did not give the raw data for overall HRQoL scores (low-certainty evidence).We found no comparative data on endocrine dysfunction; we planned to develop a brief economic commentary but found no relevant economic studies for inclusion. AUTHORS' CONCLUSIONS: Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term; however the magnitude of the risk is uncertain. Evidence on long-term neurocognitive side effects associated with chemoradiotherapy is also uncertain. Neurocognitive assessment should be an integral part of long-term follow-up in trials involving radiotherapy for lower-grade gliomas to improve the certainty of evidence regarding long-term neurocognitive effects. Such trials should also assess other potential long-term effects, including endocrine dysfunction, and evaluate costs and cost effectiveness.

Holistic needs assessment in brain cancer patients: A systematic review of available tools.

This systematic review describes tools which could be considered for use for holistic needs assessment (HNA) in brain cancer. MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO were searched. Studies were included which met the following criteria; primary research published in English which reported the development, psychometric testing or clinical utility testing of patient-reported outcome measures (PROMs) for the assessment of adult brain cancer patients' needs, problems or concerns or generic cancer needs assessment tools developed specifically on a brain cancer or brain tumour population. Nine articles describing four tools were identified. The tools were first assessed using the COSMIN protocol for systematic reviews of measurement properties and then assessed for their quality and usefulness as a holistic needs assessment tool. None of the four tools had strong psychometric properties; however, the two symptom questionnaires had better psychometric properties but would need adapted to holistically assess the multiple domains of need. The two HNA tools had only minimal psychometric testing. The lack of a tool, which adequately meets all requirements for HNA, supports the need to further development of tools to optimise this intervention.

Clinical importance of molecular markers of adult diffuse glioma.

In 2016, the WHO incorporated molecular markers, in addition to histology, into the diagnostic classification of central nervous system (CNS) tumours. This improves diagnostic accuracy and prognostication: oligo-astrocytoma no longer exists as a clinical entity; isocitrate dehydrogenase (IDH) mutant and 1p/19q co-deleted oligodendroglioma is a smaller category with better prognosis; IDH wild-type 'low-grade' glioma has a much poorer prognosis; and glioblastoma is divided into IDH mutant (with an better prognosis than pre-2016 glioblastoma) and IDH wild type (with a poorer prognosis). Previous advice based on phenotype alone will change with respect to median survival, best management plan and response to treatment. There are implications for routine neuropathology reporting and future trial design. Cases that are difficult to classify may need more advanced molecular genetic classification through DNA methylation-based classification of CNS tumours (Heidelberg Classifier). We discuss the practical implications.

Working plan for the use of patient-reported outcome measures in adults with brain tumours: a Response Assessment in Neuro-Oncology (RANO) initiative.

The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours.

Anti-angiogenic therapy for high-grade glioma.

BACKGROUND: This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti-angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs. OBJECTIVES: To evaluate the efficacy and toxicity of anti-angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease. SEARCH METHODS: We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies. SELECTION CRITERIA: RCTs evaluating the use of anti-angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy. DATA COLLECTION AND ANALYSIS: Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS: After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression-free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies. AUTHORS' CONCLUSIONS: The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti-angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies.

Symptoms in primary care with time to diagnosis of brain tumours.

Background: Brain tumours often present with varied, non-specific features with other diagnoses usually being more likely. Objective: To examine how different symptoms and patient demographics predict variations in time to brain tumour diagnosis. Methods: We conducted a secondary analysis of brain tumour cases from National Audit of Cancer Diagnosis in Primary Care. We grouped neurological symptoms into six domains (headache, behavioural/cognitive change, focal neurology, 'fits, faints or falls', non-specific neurological, and other/non-specific) and calculated times for patient presentation, GP referral, specialist consultation and total pathway interval. We calculated odds ratios (ORs) for symptom domains comparing the slowest to other quartiles. Results: Data were available for 226 cases. Median (interquartile range) time for the total pathway interval was 24 days (7-65 days). The most common presentation was focal neurology (33.2%) followed by 'fits, faints or falls' and headache (both 20.8%). Headache only (OR = 4.11, 95% CI = 1.10, 15.5) and memory complaints (OR = 4.82, 95% CI = 1.15, 20.1) were associated with slower total pathway compared to 'fits, faints or falls'. GPs were more likely to consider that there had been avoidable delays in referring patients with headache only (OR = 4.17, 95% CI = 1.14, 15.3). Conclusion: Patients presenting to primary care with headache only or with memory complaints remain problematic with potentially avoidable delays in referral leading to a longer patient pathway. This may or may not impact on the efficacy and morbidity of therapies. Additional aids are required to help doctors differentiate when to refer headaches and memory complaints urgently for a specialist opinion.

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma.

Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.

Positioning and spinal bracing for pain relief in metastatic spinal cord compression in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3 (Lee 2012) on patient positioning (mobilisation) and bracing for pain relief and spinal stability in adults with metastatic spinal cord compression.Many patients with metastatic spinal cord compression (MSCC) have spinal instability, but their clinician has determined that due to their advanced disease they are unsuitable for surgical internal fixation. Mobilising may be hazardous in the presence of spinal instability as further vertebral collapse can occur. Current guidance on positioning (whether a patient should be managed with bed rest or allowed to mobilise) and whether spinal bracing is helpful, is contradictory. OBJECTIVES: To investigate the correct positioning and examine the effects of spinal bracing to relieve pain or to prevent further vertebral collapse in patients with MSCC. SEARCH METHODS: For this update, we searched for relevant studies from February 2012 to 31 March 2015. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In Process, EMBASE, AMED, CINAHL, TRIP, SIGN, NICE, UK Clinical Research Network, National Guideline Clearinghouse and PEDro database. We also searched the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov, UK Clinical Trials Gateway (UKCTG), WHO International Clinical Trials Registry Platform (ICTRP) and Australia New Zealand Clinical Trials Registry (ANZCTR).For the original version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, CANCERLIT, NICE, SIGN, AMED, TRIP, National Guideline Clearinghouse, and PEDro database, in February 2012. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of adults with MSCC of interventions on positioning (mobilisation) and bracing. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed each possible study for inclusion and quality. MAIN RESULTS: For the original version of the review, we screened 1611 potentially relevant studies. No studies met the inclusion criteria. Many papers identified the importance of mobilisation, but no RCTs of bed rest versus mobilisation have been undertaken. We identified no RCTs of bracing in MSCC.For this update, we identified 347 potential titles. We screened 300 titles and abstracts after removal of duplicates. We did not identify any additional studies for inclusion. AUTHORS' CONCLUSIONS: Since publication of the original version of this review, no new studies were found and our conclusions remain unchanged.There is a lack of evidence-based guidance around how to correctly position and when to mobilise patients with MSCC or if spinal bracing is an effective technique for reducing pain or improving quality of life. RCTs are required in this important area.

Depression in glioma: a primer for clinicians and researchers.

Depression is one of the leading causes of global disability, and a considerable hidden morbidity among patients with glioma. In this narrative review, we summarise what is currently known about depression in glioma, the main unanswered questions and the types of studies that should be prioritised in order to find out. We conclude by calling for a prospective Phase II study of antidepressants in depressed glioma patients, to test methodologies for a multicentre randomised controlled trial.

Assessment of a brain-tumour-specific Patient Concerns Inventory in the neuro-oncology clinic.

PURPOSE: Brain tumour patients may struggle to express their concerns in the outpatient clinic, creating a physician-focused rather than a shared agenda. We created a simple, practical brain-tumour-specific holistic needs assessment (HNA) tool for use in the neuro-oncology outpatient clinic. METHODS: We posted the brain tumour Patient Concerns Inventory (PCI) to a consecutive sample of adult brain tumour attendees to a neuro-oncology outpatient clinic. Participants brought the completed PCI to their clinic consultation. Patients and staff provided feedback. RESULTS: Seventy seven patients were eligible and 53 participated (response rate = 68%). The PCI captured many problems absent from general cancer checklists. The five most frequent concerns were fatigue, fear of tumour coming back, memory, concentration, and low mood. Respondents used the PCI to formulate 105 specific questions, usually about the meaning of physical or psychological symptoms. Patients and staff found the PCI to be useful, and satisfaction with the instrument was high. CONCLUSIONS: This study demonstrates the clinical utility of the brain tumour PCI in a neuro-oncology clinic. The combination of a brain-tumour-specific concerns checklist and an intervention to focus patient agenda creates a simple and efficient HNA tool.

The end-of-life phase of high-grade glioma patients: a systematic review.

BACKGROUND: High-grade gliomas (HGG) are rare and incurable; yet, these neoplasms result in a disproportionate share of cancer morbidity and mortality. Treatment of HGG patients is directed not merely towards prolonging life but also towards quality of life, which becomes the major goal in the end of life (EOL). The latter has received increasing attention over the last decade. METHODS: We reviewed the literature related to the EOL phase of HGG patients from 1966 up to April 2012. Articles were retrieved from PubMed, Embase, Cinahl, PsycINFO and Cochrane database. We then selected papers for analysis using pre-determined inclusion criteria and subtracted information on the topics of interest. RESULTS: The search yielded 695 articles, of which 17 were classified eligible for analysis according to pre-defined inclusion criteria. Reviewed topics were symptoms and signs, quality of life and quality of dying, caregiver burden, organization and location of palliative care, supportive treatment, and EOL decision making. Nearly all identified studies were observational, with only two non-randomized intervention studies. Symptom burden is high in the EOL phase and affects the quality of life of both patient and carer. Palliative care services are more intensively used compared to other cancer patients. Cognitive deficits increase as the disease progresses, hampering communication and decision making. CONCLUSION: The EOL phase of HGG is substantially different from other patient groups, and more clinical studies in HGG on supportive medication, advance care planning and decision making are required. The organization of care, development of guidelines and interventions to decrease caregiver burden in the EOL phase are critical as well.

Antiangiogenic therapy for high-grade glioma.

BACKGROUND: The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs. OBJECTIVES: To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.• Treatment with antiangiogenic therapy versus placebo.• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy. SEARCH METHODS: Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched. SELECTION CRITERIA: RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG. DATA COLLECTION AND ANALYSIS: Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS: After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours. AUTHORS' CONCLUSIONS: In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.