In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need ...to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
Summary The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. ...The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Abstract Aims The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study ...examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. Methods QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer ( N = 891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. Results All QLQ-BN20 items correlated more strongly with their own scale ( r > 0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all α ⩾ 0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. Conclusion The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.
Advances in the management of glioblastoma Ma, Ruichong; Taphoorn, Martin J B; Plaha, Puneet
Journal of neurology, neurosurgery and psychiatry,
10/2021, Letnik:
92, Številka:
10
Journal Article
Recenzirano
Glioblastoma (GB) is the most common and most malignant primary brain tumour in adults. Despite much effort, gold standard therapy has not changed since the introduction of adjuvant temozolomide in ...2005 and prognosis remains poor. Despite this, there has been significant improvement in the surgical technology and technique, that has allowed for increased rates of safe maximal resection of the tumour. In addition, our increased knowledge of the biology of GB has revealed more potential targets, especially in the field of immunotherapy, which has been successful in revolutionising treatment of other cancers. We review the current best practice for the treatment of GB and explore some of the more recent advances in GB management from both a surgical and molecular therapeutic perspective.
Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, ...lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT).
Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.
A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio HR, 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance.
The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
Abstract
BACKGROUND
Although survival statistics in patients with glioblastoma multiforme (GBM) are well-defined at the group level, predicting individual patient survival remains challenging because ...of significant variation within strata.
OBJECTIVE
To compare statistical and machine learning algorithms in their ability to predict survival in GBM patients and deploy the best performing model as an online survival calculator.
METHODS
Patients undergoing an operation for a histopathologically confirmed GBM were extracted from the Surveillance Epidemiology and End Results (SEER) database (2005-2015) and split into a training and hold-out test set in an 80/20 ratio. Fifteen statistical and machine learning algorithms were trained based on 13 demographic, socioeconomic, clinical, and radiographic features to predict overall survival, 1-yr survival status, and compute personalized survival curves.
RESULTS
In total, 20 821 patients met our inclusion criteria. The accelerated failure time model demonstrated superior performance in terms of discrimination (concordance index = 0.70), calibration, interpretability, predictive applicability, and computational efficiency compared to Cox proportional hazards regression and other machine learning algorithms. This model was deployed through a free, publicly available software interface (https://cnoc-bwh.shinyapps.io/gbmsurvivalpredictor/).
CONCLUSION
The development and deployment of survival prediction tools require a multimodal assessment rather than a single metric comparison. This study provides a framework for the development of prediction tools in cancer patients, as well as an online survival calculator for patients with GBM. Future efforts should improve the interpretability, predictive applicability, and computational efficiency of existing machine learning algorithms, increase the granularity of population-based registries, and externally validate the proposed prediction tool.
Summary 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.
Summary Background Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in ...combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. Methods In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00689221. Findings Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8–28·8) in the cilengitide group and 26·3 months (23·9–34·7) in the control group (hazard ratio 1·02, 95% CI 0·81–1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 12% in the cilengitide group vs 26 10% in the control group), thrombocytopenia (28 11% vs 46 18%), neutropenia (19 7% vs 24 9%), leucopenia (18 7% vs 20 8%), and convulsion (14 5% vs 15 6%). Interpretation The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. Funding Merck KGaA, Darmstadt, Germany.
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.
Summary Background Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of ...standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. Methods For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days one cycle, for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov , NCT00182819. Findings Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio HR 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups ( IDH mt, with or without 1p/19q co-deletion IDH mt/codel, or IDH wild type IDH wt; p=0·013). Patients with IDH mt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 95% CI 1·21–2·87, log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDH mt/codel and IDH wt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3–4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. Interpretation Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. Funding Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
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