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BACKGROUND Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity during the treatment of glioblastoma. Here we explored the incidence and prognostic implications of lomustine modification for thrombocytopenia in recurrent glioblastoma. METHODS We retrospectively analysed thrombocytopenia, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma. RESULTS 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). 129 patients (57%) in group 1 and 187 (66%) in group 2 experienced at least one episode of thrombocytopenia; 36 patients (16%) in group 1 and 93 patients (33%) in group 2 had their treatment modified for thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with MGMT promoter-methylated glioblastoma treated with lomustine alone experienced more lomustine treatment modification than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, lomustine modification induced by thrombocytopenia was associated with inferior progression-free survival (PFS) in patients with MGMTpromoter-methylated tumors in both groups, suggesting a link to insufficient lomustine exposure. This effect was noted for overall survival, too, but only for group 2 patients. Patients with MGMT promoter-unmethylated tumors who experienced dose modification for thrombocytopenia had longer PFS and overall survival, and this effect was driven largely by group 2 patients. CONCLUSION Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced lomustine exposure in patients with MGMT promoter methylated tumors might improve outcome.

Background Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status. Methods We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA). Results By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII. Conclusion Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.

BACKGROUND Temozolomide efficacy in high-grade glioma is related to MGMTp methylation. We compared the prognostic and predictive effect of MGMTp between DNA methylation profiling (MGMT-STP27 model) and qMS-PCR in IDH1/2mt anaplastic astrocytoma patients. METHODS The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4Gy radiotherapy, radiotherapy with concurrent temozolomide, radiotherapy with 12 cycles of adjuvant temozolomide, or radiotherapy with concurrent and adjuvant temozolomide. MGMTp methylation status was assessed with the MGMT-STP27 model using 850k EPIC data, and qMS-PCR. IDH1/2 mutation status was determined with next-generation sequencing. OS was measured from randomization date. RESULTS We identified 444 IDH1/2mt anaplastic astrocytoma patients. MGMTp was methylated in 365/440 patients (83.0%) with MGMT-STP27 data, and 168/361 patients (46.5%) with qMS-PCR data. The agreement between both modalities is 59.9% (Cohen’s Kappa score 0.229). At database lock, 289 patients with MGMT-STP27 data were alive and 236 patients with qMS-PCR data. The median OS of MGMTp methylated glioma patients was 9.1 yrs [95%CI 7.5-not reached] for the MGMT-STP27 model, and not reached [95%CI 9.1-not reached] for qMS-PCR. For MGMTp unmethylated glioma patients, the median OS was 6.9 yrs [95%CI 6.2-not reached] for the MGMT-STP27 model, and 6.8 yrs [95%CI 6.2-9.7] for qMS-PCR. The HR for OS based on MGMTp methylation was 0.88 [95%CI 0.58-1.31] for the MGMT-STP27 model, and 0.72 [95%CI 0.50-1.03]) for qMS-PCR. The HR for OS after radiotherapy with any temozolomide vs radiotherapy alone for the MGMT-STP27 model was 0.53 [95%CI 0.37-0.78] for MGMTp methylated, and 0.54 [95%CI 0.25-1.18] for MGMTp unmethylated glioma patients; and for MS-PCR was 0.34 [95%CI 0.19-0.61] for MGMTp methylated, and 0.53 [95%CI 0.33-0.85] for MGMTp unmethylated glioma patients. CONCLUSION MGMTp methylation, regardless of assay, was neither prognostic nor predictive for outcome to temozolomide in IDH1/2mt anaplastic astrocytoma patients.

BACKGROUND Maintenance of functioning and wellbeing during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. MATERIAL AND METHODS We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. RESULTS 5539 patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9%-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8–5.4 months, and median time-to-deterioration between 8.2–11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. CONCLUSION HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients’ functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signalled.

BACKGROUND Temozolomide (TMZ) efficacy in high-grade glioma is related to O 6-methylguanine DNA methyltransferase promoter (MGMTp) methylation. We compared the prognostic and predictive effect of MGMTp between DNA methylation profiling (the MGMT-STP27 model) and quantitative methylation specific polymerase chain reaction (qMS-PCR) in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant (mt) anaplastic astrocytoma patients. MATERIAL AND METHODS The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy (RT), RT with concurrent TMZ, RT with 12 cycles of adjuvant TMZ, or RT with concurrent and adjuvant TMZ. MGMTp methylation status was assessed with the MGMT-STP27 model using 850k EPIC data, and qMS-PCR. IDH1/2 mutation status was determined with a next-generation sequencing panel. Overall survival (OS) was measured from date of randomization. RESULTS We identified 444 IDH1/2mt anaplastic astrocytoma patients of which MGMT-STP27 data was available for 440 patients (99.1%), qMS-PCR data for 361 patients (81.3%), and both for 357 patients (80.4%). MGMTp was methylated in 365 patients (83.0%) for the MGMT-STP27 model, and 168 patients (46.5%) for qMS-PCR. The agreement between the MGMT-STP27 model and qMS-PCR is 59.9% with a Cohen’s Kappa score of 0.229. At database lock, 289 patients with MGMT-STP27 data were still alive and 236 patients with qMS-PCR data. The median OS of MGMTp methylated glioma patients was 9.1 yrs [95 % confidence interval (CI) 7.5-not reached] for the MGMT-STP27 model, and not reached [95 % CI 9.1-not reached] for the qMS-PCR data. For MGMTp unmethylated glioma patients, the median OS was 6.9 yrs [95% CI 6.2-not reached] for the MGMT-STP27 model, and 6.8 yrs [95% CI 6.2–9.7] for the qMS-PCR data. The hazard ratio (HR) for OS based on MGMTp methylation was 0.88 [95% CI 0.58–1.31] for the MGMT-STP27 data, and 0.72 [95% CI 0.50–1.03]) for the qMS-PCR data. The HR for OS after RT with any TMZ vs RT alone for the MGMT-STP27 model was 0.53 [95% CI 0.37–0.78] for MGMTp methylated, and 0.54 [95% CI 0.25–1.18] for MGMTp unmethylated glioma patients; and for the MS-PCR data was 0.34 [95% CI 0.19–0.61] for MGMTp methylated, and 0.53 [95% CI 0.33–0.85] for MGMTp unmethylated glioma patients. CONCLUSION MGMTp methylation, regardless of assay, was neither prognostic nor predictive for outcome to temozolomide in IDH1/2mt anaplastic astrocytoma patients.

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.

BACKGROUND: TG02 is an oral multi-cyclin dependent kinase (CDK) inhibitor that is thought to inhibit tumor growth mainly through CDK9-dependent depletion of oncoproteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma (up to 80%). Several studies including analyses of patient-derived glioma cell lines have demonstrated profound inhibitory activity (IC50 range = 25–150 nM). Clinical pharmacokinetics from a phase 1b study in multiple myeloma patients demonstrate that TG02 exposures in humans are sufficient for achieving inhibitory concentrations required in the majority of the glioma cell lines tested. Preclinical studies in mice have demonstrated that TG02 is a good candidate for development in gliomas. METHODS: Based on these data, the EORTC Brain Tumor Group, in cooperation with Tragara, is currently conducting the phase 1b STEAM trial (EORTC 1608), a three parallel group (A,B,C) open-label, non-randomized, multicenter study. The recommended phase II dose of TG02 in elderly patients with IDH1R132H-non mutant newly diagnosed glioblastoma will be determined in a classical 3 + 3 design dose-escalation and safety study of TG02 in combination with either hypofractionated radiotherapy (RT) or temozolomide (TMZ) in arms A and B. Patient allocation to treatment in arms A and B will be determined by MGMT promoter methylation status centrally determined according to EANO guidelines for the treatment of elderly patients with glioblastoma. Arm C will explore single agent TG02 activity in anaplastic astrocytoma or glioblastoma at first relapse after initial treatment with TMZ/RTTMZ with a primary endpoint of progression-free survival at 6 months. Secondary objectives include efficacy, quality of life, safety, and correlation with molecular markers. The study is currently open in 2 sites and shall be opened until SNO in 5 additional EORTC sites in Europe. Patient enrolment is planned to start in June 2018. An update will be provided at the SNO conference. NCT03224104

BACKGROUND: It is currently unknown whether increasing radiotherapy volumes have a negative impact on the health-related quality of life (HRQoL) of low-grade glioma (LGG) patients on the short-term. The aim of this study was to examine if the size of the target volume is independently associated with HRQoL. MATERIAL AND METHODS: Patients treated with radiotherapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033–26033 study, and who completed a baseline HRQoL form, were included. This phase 3 trial of radiotherapy vs. temozolomide chemotherapy in high-risk LGG requiring treatment did not show a progression free survival difference. HRQoL was measured at baseline and every 3 months thereafter until progression, using the EORTC QLQ-C30 core questionnaire and QLQ-BN20 brain module. Associations between radiation volumes and (changes in) four preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue) were determined. Also, it was determined if radiation volumes were independently associated with a change in HRQoL over time. RESULTS: A total of 195 out of the 240 patients randomized to radiotherapy (81.3%) were included in this analysis. The brain volume receiving radiotherapy was not associated with (changes in) HRQoL during the first 24 months after radiotherapy. Over time, radiation volumes were also not independently associated with HRQoL. Although treatment with radiotherapy resulted in worse functioning, and more fatigue three months after treatment, pre-treatment levels were reached thereafter and maintained during further follow-up. Particularly the occurrence of tumour progression was found to be associated with clinically relevant worse social functioning (Beta: -13.7, 95% CI:-19.5 to -7.9), and more fatigue (Beta: 13.2, 95% CI:7.8–18.5) during 24 months follow-up. CONCLUSION: The volume of brain receiving focal radiotherapy does not seem to be an important determinant for the level of HRQoL in high-risk LGG patients on the short-term. From this point of view, safety margins do not need to be reconsidered. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.

BACKGROUND Between 1995 and 2002 the EORTC Brain Tumor Group conducted a prospective phase III study on adjuvant procarbazine, CCNU and vincristine (PCV) chemotherapy in anaplastic oligodendroglioma (AOD). A mature follow-up presented in 2012 showed survival benefit of the addition of PCV, in particular in 1p/19q co-deleted tumors and tumors with MGMT promoter methylation. We now present very long term follow-up. MATERIALS AND METHODS Patients were eligible if locally diagnosed with a newly diagnosed AOD. They were randomized between radiotherapy (RT, 33 x 1.8 Gy) and the same RT followed by 6 cycles PCV (RT/PCV). Primary endpoints were overall survival (OS) and progression free survival (PFS). 1p/19q status (FISH) was determined in 300 patient. Kaplan- Meier technique and Cox modeling were used for long term survival analysis. Primary analyses were adjusted for known prognostic factors. For other analyses no adjustment was performed. RESULTS With 368 patients included, a median follow-up of 18.4 years and 307 (83%) survival events, median and 20-year survival after RT/PCV versus RT alone were 42.3 mo and 16.8% vs 30.6 months and 10.1% (HR 0.78; 95% CI (0.63, 0.98), adjusted p=0.06). Eighty patients were 1p/19q codel of which 26 (33%) were still alive, in this subgroup median and 20-year survival after RT/PCV versus RT alone were 14 years and 37.1% versus 9.3 years and 13.6% (HR 0.60, 95% CI (0.35, 1.03), unadjusted p=0.06). Twenty year PFS in 1p/19q codel was 31.3% in RT/PCV treated patients and 10.8% in RT only treated patients (HR 0.49, 95% CI (0.29, 0.83), unadjusted p=0.007). In the 1p/19q codel subgroup age, WHO PS and necrosis at pathology were identified to be of independent prognostic value for OS. CONCLUSION This long term analysis confirms the earlier conclusions and provides data on long term survival in this patient group. In 1p/19q codel patients treated with RT/PCV, the 20-year PFS and OS rates are 31% and 37% respectively.

BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma. MATERIAL AND METHODS EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status >70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT→TMZ) alone or TMZ/RT→TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095

Low-grade glioma (LGG) is a heterogeneous group of primary, diffuse, and slowly growing glial brain tumors. These tumors often remain clinically stable for many years, and patients are commonly only followed clinically without specific antitumor therapy. Based on retrospective studies suggesting an improved survival with early, extensive, and maximal tumor resections, radical surgery is often advocated. Prospective controlled studies evaluating the role of surgery are lacking, and a large part of the benefit presumed from extensive resection may be due to patient selection. If tumor location makes the surgery difficult or even impossible, a biopsy is performed to ascertain the nature of the tumor and establish a pathological diagnosis. Immediate (postoperative) radiotherapy has not been shown to offer an advantage in overall survival (OS) over deferred radiotherapy; although progression-free survival (PFS) is lengthened, the optimal timing remains debatable. There is no apparent effect of dose; 2 randomized studies by the European Organisation for Research and Treatment of Cancer (EORTC) and of the North Central Cancer Treatment Group (NCCTG)/Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG) Intergroup showed no significant difference in survival when researchers compared lower and higher irradiation doses (45 vs 59.4 Gy and 50.4 vs 64.8 Gy, respectively).1,2,8 The role of postoperative chemotherapy alone or in combination with radiation therapy remains investigational.3 Individual prognosis of patients is highly variable. In order to choose the best strategy for a patient among the various treatment options, prognostic models and scores can be useful. A major limitation in addressing prognostic models for LGG is the considerable interobserver variability in both the grading and the typing of these tumors.4,5 The widely used EORTC prognostic scoring model for LGG was based on 2 prospective randomized clinical trials. However, patient inclusion into these trials relied upon a diagnosis made by the local pathologist, which was often not confirmed by central pathology review.6 The external validity of the EORTC scoring system was recently evaluated in a dataset of LGG patients treated in a North American Intergroup trial (NCCTG 86-72-51).7 In that dataset, the distinction between the low-risk and the high-risk group was predominantly determined by the prognostic impact of histology and tumor size; other factors, like age and extent of surgery, did not contribute significantly. A major difference between the US and European trials was the mandatory central pathology review prior to inclusion in the American trials. Thus, we reanalyzed the pooled data from the 2 EORTC studies, restricting the analysis to patients with LGG whose histology had been confirmed upon central pathology review. Patients with histologies other than grade II glioma and patients from whom no tumor tissue was available for central review were excluded. We subsequently assessed the external validity of the EORTC studies with the individual patient data from large studies conducted by 2 US cooperative groups (RTOG and NCCTG).8,9 Based on this analysis, we developed prognostic calculators for PFS and OS that provide estimates for both median and fixed time probabilities of survival.

BACKGROUND: Depatux-M is an antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of EGFR bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified (amp) recurrent glioblastoma treated with Depatux-M in combination with temozolomide. METHODS: Eligible were patients with centrally confirmed EGFRamp glioblastoma at 1st recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic sampling was part of the study design, all samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFRamp was re-analysed using next generation sequencing. RESULTS: In February 2018, an updated OS comparison performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting the follow-up from Aug 2018 will be presented, obtained more than 24 months after the end of accrual. CONCLUSION: This updated OS analysis of Depatux-M in combination with temozolomide confirmed the OS improvement in EGFRamp recurrent glioblastoma. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS, but high levels of EGFR amplification at first diagnosis were not.

INTRODUCTION: Current efforts to improve patient survival in recurrent glioblastomas (GBMs) are often based on targeting the tumors acquired genetic changes. However, most molecular data is derived from the initial tumor: resections of recurrent GBMs are seldom performed. This study aims to assess whether genetic traits of initial GBMs are still present at recurrence. METHODS: DNA/RNA was isolated from pairs of initial and recurrent Stupp-treated GBM tumor samples (FFPE) and sequenced on a panel of 365 cancer genes. MGMT promotor methylation was determined by MS-PCR, EGFRvIII by RT-PCR and TERT-promotor mutations by SNaPshot. RESULTS: 276 patients from ten medical centers in six countries were identified with median age of 54.1 years. Median survival was 23.7 months, and median time to second surgery 13.0 months. Only 10 of 186 sequenced matched tumor pairs were IDH-mutated (5.4%). Overall, genetic traits of initial GBMs were stable with a median retention rate of coding mutations of 81.8%. Similarly, copy number changes (CNVkit/GISTIC) generally were retained at tumor recurrence. However, the retention rate was also ~80% in all of the major GBM driver pathways (TP53 signaling, RAS-RAF-MEK-ERK, RTK signaling). This is important as decreases 20% of loss of a marker requires a doubling of the number of included patients to achieve a similar power (assuming an objective response rate of 40% as a positive outcome). One noticeable change was a loss of TERT-promoter mutations in 7.5% of recurrent samples. Only four tumors were hypermutated (> 100 coding mutations) at recurrence, though more samples (n=12) acquired mutations in MSH2 and MSH6. Only one EGFR-amplified tumor was hypermutated. CONCLUSION: EGFR-amplified GBMs seldom transform into hypermutated tumors which suggests immune-checkpoint inhibitors have limited clinical use in recurrent GBMs. Re-sampling should be considered prior to inclusion in targeted therapy trials to ensure proper patient selection.

INTRODUCTION: Symptom management in glioma patients remains a challenge, as patients suffer from various concurrent occurring symptoms. This study aimed to identify symptom clusters and to examine the relation between these symptom clusters and functioning. METHODS: We prospectively included individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with EORTC QLQ-C30 and QLQ-BN20 questionnaires. The magnitude of the associations between symptoms were examined with Spearman correlation coefficients and correlation matrices. Hierarchical cluster analyses (looking at euclidean distances) were performed to identify symptom clusters. Multivariable regression analyses were performed to analyze associations between the symptom clusters and functioning, adjusted for confounding variables. RESULTS: Data of 3595 newly diagnosed glioma patients who completed the questionnaires before randomization indicated that many patients (44%) suffered from 5–10 symptoms simultaneously. The most prevalent symptoms were fatigue, drowsiness and motor dysfunction, experienced by 86%, 59% and 55% of the patients respectively. Five symptom clusters were identified with hierarchical cluster analyses: motor cluster, fatigue cluster, headache cluster, gastrointestinal/seizures cluster and hair loss/itchy skin cluster. Having symptoms in the motor cluster had a clinically relevant and significant negative influence (≥10points difference) on the global health status/quality of life scale, and physical, role, cognitive and social functioning (Beta’s ranged from -10.9 to -18.6, all p

Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR amp were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology. Neuro-Oncology 11, 737-746, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00260, February 17, 2009. URL http://neuro-oncology.dukeiournals.org; DOI: 10.1215/15228517-2009-011)

LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Several small uncontrolled retrospective case series as well as a post-hoc analysis of the registration trial for temozolomide in newly diagnosed glioblastoma (Weller et al., 2011) have indicated an association between valproic acid (VPA) use and improved outcome in patients with newly diagnosed glioblastoma. To confirm the hypothesis generated based on the analysis of the temozolomide registration trial, we performed a combined analysis of a survival association of AED use at the start of chemoradiotherapy with temozolomide in the pooled patient cohort (n = 1869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (NCT00943826), RTOG-0825 (NCT00884741), CENTRIC (NCT00689221) and CORE (NCT00813943). Progression-free (PFS) and overall survival (OS) were compared between (i) VPA versus no AED, (ii) VPA versus enzyme-inducing (EI)-AED, or (iii) VPA versus other non-EI-AED (without VPA). Results of Cox regression models stratified by trial and adjusted baseline prognostic factors including O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status were interpreted. The same analyses were performed with levetiracetam (LEV). VPA use at the start of chemoradiotherapy was not associated with improved PFS or OS compared with patients receiving no AED (PFS: hazard ratio (HR) = 0.92, 95% confidence interval (CI) 0.75-1.13, p = 0.41; OS: HR = 1.00, 95% CI 0.80-1.25, p = 0.95), EI-AED (PFS: HR = 0.95, 95% CI 0.74-1.21, p = 0.62; OS: HR = 1.02, 95% CI 0.0.77-1.33, p = 0.93) or non-EI-AED (PFS: HR = 1.02, 95% CI 0.80-1.3, p = 0.92; OS: HR = 1.06, 95% CI 0.83-1.35, p = 0.67). Similarly, no association with outcome was seen for LEV use. This pooled analysis did not validate an association of VPA or LEV use with improved survival, challenging the need for a full phase III trial exploring the repurposing of VPA or LEV as add-on to the standard of care treatment of newly diagnosed glioblastoma.

BACKGROUND: Molecular holds promise for an improved classification of glial tumors. We analyzed samples of patients enrolled in EORTC study 26951 on adjuvant PCV in anaplastic oligodendroglial tumors to evaluate 1. The clinical significance of glioma classification with Next Generation Sequencing (NGS); and 2. The prognostic significance of CIC and FUBP mutations. MATERIAL AND METHODS: EORTC 26951 investigated adjuvant PCV in locally diagnosed anaplastic oligodendroglial tumors. NGS was performed on archival formalin fixed paraffin embedded (FFPE) samples using the Ion Torrent Personal Genome Machine for simultaneous detection of mutations in the genes for ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN, and TP53 and hot spot mutation regions in BRAF, H3F3A, IDH1, IDH2 and PIK3CA as well as imbalances on chromosome 1p, 10q, 7 en 19q. TERT mutations were assessed with PCR. RESULTS: At the time of abstract submission 89 cases have been investigated, more samples are being processed. In 62 tumors an IDH1 mutations was found, in 2 an IDH 2 mutation. Forty-eight tumors (54%) were 1p/19q codeleted, 29 (60%) of these had CIC mutations and 20 (42%) had FUBP mutations. All but one 1p/19q codeleted tumors showed TERT mutations. Ten tumors showed ATRX mutations, 5 also had PTEN mutations. Median OS was 136 months for CIC mutated 1p/19q co-delete tumors, and 95 months for CICwt tumors (p = 0.17); FUBP mutations showed no relation with OS. TERT mutations were found in 60 tumors (67%), OS in TERT mutated but 1p/19q intact tumors was 12 months. IDH mutations, TERT mutations and 1p/19q co-deletion were the most significant prognostic factors, distinguishing between groups with significantly different OS. CONCLUSIONS: The ongoing expansion of this series will show if CIC mutations have prognostic significance. Targeted NGS even on archival FFPE allows a clinically relevant prognostic classification of glioma, while simultaneously identifying relevant druggable targets.

BACKGROUND: With the rapid discovery of prognostic and predictive molecular parameters for glioma, the status of histopathology in the diagnostic process should be scrutinized. The present project aimed at the construction of an evidence-based diagnostic algorithm for gliomas. To reach this goal, histological features were scrutinized for their prognostic relevance and acceptable inter-observer variability. In addition, molecular markers should be validated for their prognostic power and possible overlap when simultaneously applied. METHODS: The pathology slides of EORTC trials 26951 and 26882 were scanned for virtual microscopy, an electronic scoring form was created and a panel of six pathologists was formed to independently evaluate the slides. The molecular analysis for IDH1, 1p/19q loss; EGFR amplification; loss of chromosome 10 and 10q, gains of chromosome 7 and hypermethylation of the promoter of MGMT were available for appr. half of cases. The slides were divided in a test (discovery) set (n = 500) and a validation set (n = 300). All follow-up data were available at the EORTC data center in Brussels and the results were statistically tested with the aim to create and validate the diagnostic algorithm. RESULTS: In 66% of cases consensus of overall diagnosis was present. Cox regression analysis of consensus histological features and molecular markers revealed the prognostic significance of the parameters necrosis, cell density, mitotic index, loss 1p/19q and IDH1 mutation. A diagnostic algorithm consisting of relevant (consensus and prognostically significant) histological features and molecular markers was identified by CART analysis and consisted of 2 molecular markers and 1 histological feature. The order of prognostic power was: 1p/19q loss; EGFR amplification; astrocytic morphology, and 4 diagnostic nodes were identified. Validation of the nodes in the validation set yielded 4 significantly different survival curves (Overall Wald test p < 0.0001). CONCLUSION: we succeeded in the creation of a timely combined histologic and molecular diagnostic algorithm.