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2042Background: Around 40% of glioblastomas exhibit amplification of the epidermal growth factor receptor (EGFR) gene; half of these tumors carry a specific genetic rearrangement characterized by deletion of exons 2-7 (EGFRvIII). The prognostic role of EGFRvIII in patients with EGFR-amplified glioblastoma and its expression in recurrent as opposed to newly diagnosed glioblastoma have not been defined. Such data are highly relevant for the clinical development of novel EGFRvIII-targeting agents. Methods: EGFR-amplified glioblastomas from 109 patients treated according to standard of care were assessed for EGFRvIII expression and data were correlated with outcome. Pairs of primary and recurrentglioblastomas from 38 of these patients (including 25 patients with EGFRvIII-positive tumors) and from 33 glioblastoma patients without EGFR amplification were evaluated for changes in EGFR amplification and EGFRvIII expression at recurrence. Results: Among 109 patients with EGFR-amplified primary glioblastoma, 63 had...

2007 Background: WHO grade II and III cerebral gliomas represent a major challenge for histological classification and clinical management. Here, we aimed to improve prognostically relevant patient...

2014 Background: The prognosis of glioblastoma remains poor: only a minority of patients experience long-term survival beyond three years after diagnosis. Previously identified predictors of long-t...

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

2045 Background: Aim of this prospective longitudinal study was to evaluate whether 18FET-PET allow to monitor and quantify the therapeutic effects of surgery, radiotherapy and chemotherapy in newly diagnosed glioblastoma and whether 18FET-PET can provide additional prognostic information on response to therapy and outcome. Methods: 92 patients with newly diagnosed glioblastoma considered eligible for radiochemotherapy (RcX) were included; diagnosis was obtained by biopsy (n=46) or resection (n=46). Patients were to undergo 18FET-PET and cocomitant MRI scans prior to surgery, following RcX and as well as after three cycles of adjuvant temozolomide (TMZ). At each time point, biological tumor volume (BTV), maximal 18FET uptake as ratio to background (SUVmax/BG), and tumor uptake kinetics (TAC) were obtained. Overall survival (OS) was primary endpoint, progression-free survival (PFS) as defined by MRI using Macdonald criteria was a secondary endpoint. ROC analyses were done to determine optimal cut-off values of 18FET-PET parameters for survival outcome. To identify predictors for OS/PFS, Cox regression analysis was performed. Results: 79 patients were eligible for further evaluation. ROC analysis revealed cut-off values for pre-RCX BTV (9.5 ccm) and SUVmax/BG (2.95) with a sensitivity and specificity of both 70% for BTV and 68/73% for SUVmax/BG. Both pre-therapeutic BTV and SUVmax/BG were associated with PFS and OS (p18FET TAC pattern and its changes were related to OS and PFS. Conclusions: Serial 18FET-PET imaging in glioblastoma before and after concomitant radio-/chemotherapy is a highly powerful tool to provide prognostic information for the outcome in newly diagnosed glioblastoma patients. These findings might help to personalize therapy and response evaluation in forthcoming clinical investigations. Clinical trial information: NCT01089868.

2000 Background: In a few years more than half of the patients with glioblastoma will be older than 65 years of age and thus be classified as elderly. The current standard of care in elderly patients with glioblastoma (GB) or anapestic astrocytoma (AA) is resection or biopsy followed by involved-field radiotherapy (RT). The role of primary chemotherapy is poorly defined. The NOA-08 trial compared efficacy and safety of RT to temozolomide (TMZ) in patients with newly diagnosed AA or GB. Methods: Patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score > 60 were randomized to receive RT or TMZ. The primary endpoint was overall survival (OS). The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Results: Patient characteristics in the intention-to-treat population [N=373 (178 patients RT, 195 patients TMZ)] were balanced. All histologic diagnoses (11% AA and 89% GB) were centrally confirmed. Median OS [HR=1.09 (95% CI: 0.84-1.42)] and event-free survival (EFS) [hazard ratio (HR)=1.15 (0.92-1.43)] of TMZ versus RT did not differ between both arms. Non-inferiority of TMZ compared with RT was significant (p6-methylguanine DNA-methyltransferase (MGMT) promoter methylation in tumor tissue was associated with prolonged OS [HR=0.67 (0.38-1.29)]. Patients with MGMT promoter methylation had longer EFS when treated with TMZ (8.4 months [5.5-11.7] versus RT (4.6 [4.2-5] months) whereas patients without MGMT promoter methylation had longer EFS when treated with RT (4.6 [3.7-6.3] versus 3.3 [3-3.5] months). This effect persisted for OS. Conclusions: NOA-08 demonstrates the non-inferiority of TMZ compared with RT in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ.

2037 Background: Outside of controlled trials, the occurrence of objective responses (OR) to chemotherapy in glioma patients is poorly characterized. Further, the predictive value of OR for progression-free survival (PFS) and overall survival (OS) in glioma patients is unclear. Methods: In this study we screened the German Glioma Network Database for patients that had received any chemotherapy for recurrent glioma from 2004-2008. Patients with a gross total resection of the recurrent tumor, patients receiving radiotherapy for the recurrent tumor and patients with spinal gliomas were excluded. 655 chemotherapies in 487 patients were identified. The prospectively documented responses to these chemotherapies were reevaluated in the 8 participating centers and 69 ORs (corresponding to OR in 10.5% of all chemotherapies) were identified (partial responses, PR or complete responses, CR, according to the original Macdonald criteria). For 52 of these (75.4% of all cases with OR) imaging data were evaluable for cen...

2001 Background: Methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter identifies a subpopulation of glioblastoma patients with a more favorable course of disease and predicts a...

LBA2001 Background: The median survival time for elderly patients (pts) with malignant gliomas is in the range of a few months. Radiotherapy (RT) is the standard treatment and superior to best supportive care both with respect to progression-free and overall survival. The benefit derived from surgery and RT is modest, and both treatments are less well tolerated in elderly pts than in the young. The availability of a potentially effective pharmacological agent, temozolomide (TMZ), for malignant glioma, which exhibits a favorable safety profile, necessitated a reconsideration of the widespread therapeutic nihilism with malignant glioma in the elderly. Methods: The NOA-08 trial of the Neurooncology Working Group (NOA) of the German Cancer Society compared standard postsurgical involved-field RT to a dose of 54-60 Gy, in pts with anaplastic astrocytoma or glioblastoma > 65 ys with a Karnofsky performance score ≥ 60, to TMZ in an one week on/one week off schedule at 100 mg/m2 with dose modification in 25 mg steps in both directions. The primary endpoint was the median survival time (OS) during the follow-up in the 12 months after date of operation. The trial sought to demonstrate the non-inferiority of TMZ compared with RT. Regarding a maximal difference of 25% between both treatment arms in OS as being equivalent, 2 x 206 pts were randomized between May 15, 2005 and Nov 2, 2009 in 22 German and one Suisse sites to provide 80% power to achieve significance at a one-sided level of 0.05. Thirty-nine patients were excluded from the intention-to-treat (ITT) population because no therapy was applied (n=22) or withdrawal of informed consent (n=17). Results: All histological diagnoses were centrally confirmed. Pts characteristics were balanced between arms in the ITT population (n=373) except for more resections and more anaplastic astrocytomas in the RT arm. The non-inferiority of TMZ was not shown. In contrast, pts in the TMZ arm had an increased risk of death (HR=1.24 [95% CI: 0.94-1.63]) compared to pts in the RT arm. The rate of adverse and serious adverse events was higher in the TMZ arm. Conclusions: This trial fails to show the non-inferiority of dose-intensified TMZ alone compared with RT alone in the primary treatment of older pts with malignant glioma. Unlike anaplastic glioma in the younger patient population, RT cannot be safely deferred in the treatment of elderly patients with anaplastic astrocytoma or glioblastoma. Whether RT plus TMZ is superior to RT alone, is addressed in the ongoing companion trial conducted by NCIC, EORTC and TROG. [Table: see text] [Table: see text]

8579 Background: Methotrexate (MTX) is the most efficient chemotherapeutic drug in primary central nervous system lymphoma (PCNSL); it directly interferes with methionine metabolism. Patients and Methods: Eight functional polymorphic variants influencing methionine metabolism were investigated in 65 PCNSL patients and were analyzed for their impact on the occurrence of confluent CNS white matter changes (WMC) (Pearson’s Chi-square test and multinominal regression analysis) and for their influence on survival (univariate Log Rank and multivariate COX regression analyses). Results: Twenty/65 (31%) patients developed WMC, which was significantly predicted by the genotype of methylenetetrahydrofolate reductase c.1298A>C (p.E429A; patients with WMC, AA/AC/CC: 0.80/0.10/0.10; patients without WMC: 0.40/0.47/0.13; nominal logistic regression: χ2=11.54; p=0.003). In addition, the transcobalamin 2 variant c.776C>G (p.P259R) influenced the occurrence of WMC (patients with WMC: 0.20/0.45/0.35; patients without WMC: ...