Anaplastic Oligodendroglial Tumors Research Articles

QOL-18. HIGHER VINCRISTINE DOSES CORRELATE WITH LONGER OVERALL SURVIVAL: A POST-HOC ANALYSIS OF PARTICIPANTS RECEIVING PCV ON RTOG 9402

Abstract RTOG 9402 demonstrated procarbazine (P), lomustine (CCNU/C), and vincristine (V), collectively PCV, added to radiation therapy significantly improved survival for patients with newly diagnosed anaplastic oligodendroglial tumors. The improvement was most pronounced in 1p19q codeleted cases, and to a lesser extent, IDH-mutant cases, with no survival benefit in cases with neither biomarker. Analogous results were observed in other phase III trials. However, vincristine (V) can cause substantial toxicity and requires intravenous administration, both negatively affecting quality of life, with debatable contribution to PCV efficacy. As a randomized trial comparing PCV to PC is unlikely to be conducted, we explored correlations between survival and V-dosing in patients randomized to PCV in RTOG 9402. We performed post-hoc analyses of all evaluable participants (n = 143) randomized to PCV on RTOG 9402, supplemented by restricting the analyses to the chemosensitive molecular subsets (IDH-mutant and/or 1p/19q codeleted, n = 118). Total V dose by quartile (Q) was calculated. Survival from six months post-randomization was compared among V dose groups, adjusting for age, extent of resection (EOR), and Karnofsky Performances Status (KPS) in a Cox proportional hazards model. Higher V dose received correlated with longer survival in multivariate analyses (n = 134, median-Q3 vs. < Q1, HR 0.40 (0.22, 0.73), p = 0.003; ≥Q3 vs. < Q1, HR 0.39 (0.22, 0.72), p = 0.002). Excluding chemoresistant cases (IDH wild-type/not codeleted), survival was also significantly longer in evaluable participants receiving the highest doses of vincristine (≥Q3 vs. < Q1 HR 0.42 (0.21,0.81), p = 0.01). In this post-hoc analysis, higher overall V-dose received correlated with longer survival in evaluable patients with anaplastic oligodendroglial tumors receiving PCV chemotherapy in RTOG 9402. Of note, as vincristine dosing was not assigned by randomization, confounding due to differences in patient characteristics among V dose groups cannot be ruled out. Caution should be exercised when considering discarding V from the PCV regimen.

Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

Predicting different pathological grades with contrast-enhanced MR imaging in oligodendrogliomas

Medical image processing and its quantitative analysis plays a vital role in several clinical scenarios, such as diagnosis as well as treatment. The results of this study show that there are 478 mRNAs differentially expressed in low grade as compared to anaplastic oligodendroglial tumor (2 Fold greater, p < 0.05) group. These genes participated in Gene Ontology and KEGG pathways such as cell migration, cell motility, and cytokine-cytokine receptor interaction. Oligodendroglial classification models derived from advanced imaging will improve the accuracy of tumor grading, provide prognostic information, and have potential to influence treatment decisions.

Isocitrate dehydrogenase (IDH) status prediction in histopathology images of gliomas using deep learning

Mutations in isocitrate dehydrogenase genes IDH1 and IDH2 are frequently found in diffuse and anaplastic astrocytic and oligodendroglial tumours as well as in secondary glioblastomas. As IDH is a very important prognostic, diagnostic and therapeutic biomarker for glioma, it is of paramount importance to determine its mutational status. The haematoxylin and eosin (H&E) staining is a valuable tool in precision oncology as it guides histopathology-based diagnosis and proceeding patient’s treatment. However, H&E staining alone does not determine the IDH mutational status of a tumour. Deep learning methods applied to MRI data have been demonstrated to be a useful tool in IDH status prediction, however the effectiveness of deep learning on H&E slides in the clinical setting has not been investigated so far. Furthermore, the performance of deep learning methods in medical imaging has been practically limited by small sample sizes currently available. Here we propose a data augmentation method based on the Generative Adversarial Networks (GAN) deep learning methodology, to improve the prediction performance of IDH mutational status using H&E slides. The H&E slides were acquired from 266 grade II-IV glioma patients from a mixture of public and private databases, including 130 IDH-wildtype and 136 IDH-mutant patients. A baseline deep learning model without data augmentation achieved an accuracy of 0.794 (AUC = 0.920). With GAN-based data augmentation, the accuracy of the IDH mutational status prediction was improved to 0.853 (AUC = 0.927) when the 3,000 GAN generated training samples were added to the original training set (24,000 samples). By integrating also patients’ age into the model, the accuracy improved further to 0.882 (AUC = 0.931). Our findings show that deep learning methodology, enhanced by GAN data augmentation, can support physicians in gliomas’ IDH status prediction.

ACTR-13. FINAL RESULTS WITH CHEMORADIOTHERAPY FOR ANAPLASTIC OLIGODENDROGLIAL TUMORS FROM NRG ONCOLOGY/RTOG 9402

Abstract BACKGROUND Adding intensive-procarbazine, lomustine, and vincristine (iPCV) to radiotherapy (RT) prolonged progression-free (PFS) and overall survival (OS) for patients with 1p19q codeleted anaplastic oligodendroglial tumors (AOTs); some benefit was also observed for IDH-mutant non-codeleted cases (Cairncross et al 2013, 2014, 2016). Now, 25 years after study activation, we updated survival, further assessed IDH as a predictive biomarker, and are exploring the benefit from vincristine. METHODS Eligible adults (KPS ≥ 60, adequate end-organ function) were randomized to pre-RT iPCV (4 cycles x 6 weeks each) vs. RT alone, stratified by age (&lt; or ≥ 50), KPS (60–70 or ≥ 80), and level of anaplasia. Histology (anaplastic oligodendroglioma/oligo-astrocytoma required) and biomarkers (IDH and 1p19q, post-hoc) were determined centrally. Survival was estimated by Kaplan-Meier and Hazard Ratios (HRs) by Cox-regression. RESULTS Overall (n=289), median follow-up was 16.4 years vs. 11.3 years at last report. In codeleted cases, 40% randomized to iPCV remained alive vs. 53% at last report; 5, 10, and 14 year-PFS and -OS rates were 62%, 50%, 41% and 70%, 57%, 46%, respectively; and iPCV unequivocally prolonged PFS (median 9.8 vs. 2.9 years, HR 0.46, 95% CI 0.3–0.7, p&lt; 0.001) and OS (median 13.2 vs. 7.3 years, HR 0.61, 95% CI 0.40–0.94; p=0.02). With IDH mutation but without codeletion (n=66), iPCV prolonged PFS (median 2.8 vs. 1.9 years, HR 0.58, 95% CI 0.34–0.99, p=0.046); OS was longer with a trend for significance (median 5.5 vs. 3.3 years, HR 0.6, 95% CI 0.34–1.03, p=0.06) on this underpowered exploratory post-hoc analysis. CONCLUSION For codeleted AOTs, long-term analyses confirmed that pre-RT iPCV produced meaningful and significant prolongations of PFS and OS. With IDH mutation but without codeletion, iPCV significantly prolonged PFS and showed a trend for prolonged OS. The value of vincristine is being assessed. Supported by NCI grants U10CA180868, U10CA180822, U24CA196067, and UG1CA189867.

P03.09 Real world management and prognosis of glioma patients:SYSUCC report from China

Abstract Background: The conventional way of patient treatment should be following guidelines. While in clinical practice, patients received treatments very often away from suggested guideline. In this report, we reviewed glioma patients received real world treatment at Sun Yat-sen University Cancer Center (SYSUCC) and results of this patient series. Methods: Total of 1215 glioma patients received surgery at SYSUCC from 2000 to 2017 were enclosed for analysis. The pathologic diagnosis of patients has followed WHO classification (initially 2007 standard, than 2016 standard). Results: A total of 1001 newly diagnosed brain glioma patients were analyzed, including 90 cases WHO grade I, 307 grade II, 239 grade III and 365 grade IV. The median age of onset was 14 (1–75), 35 (2–69), 41 (8–82) and 50 (2–86) years old, respectively, for grade I, II, III and IV glioma patients. Tumor total resection was achieved in 567 patients (57.5%). Among all patients, 331 high-grade gliomas (54.8%) and 159 low-grade glioma (40.1%) received radiotherapy, whereas 285 high-grade gliomas (47.1%) and 80 low-grade tumors (20.2%) received chemotherapy. Among high-grade gliomas, the median OS of glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglial tumors were 17.7 months (15.7–19.7 months), 33.7 months (24.0–43.4 months) and 110.6 months (43.5–177.7 months), respectively, whereas the median OS of low-grade gliomas was not reach. The 5-year survival rate of grade I, II, III and IV gliomas was 94.7%, 73.7%, 45.1% and 18.6%, respectively. Multivariate analysis identified that onset age, Karnofsky performance status, tumor location, preoperative seizure, pathological subtype, resection extent and post-surgical treatment were independent predictors of OS for patients with high-grade gliomas. Patients received post-surgical radiotherapy and (or) chemotherapy had better survival than those without adjuvant treatment (grade III: 53.3 vs. 20.6 months, p =0.012; grade IV: 22.9 vs. 12.3 months, p &lt; 0.001). For low-grade gliomas, patients’ age, Ki-67 index, tumor subtype and resection extent were associated with clinical outcomes. Conclusions: Glioma patients received treatments do not always following guidelines in clinical practice. Although standard care for patients may beneficial for prognosis, personalized treatment may more acceptable for patients and even resulting better outcome which should keep in mind in routine clinical practice.

Regional specificity of 1p/19q co-deletion combined with radiological features for predicting the survival outcomes of anaplastic oligodendroglial tumor patients.

In this study we aimed to identify the anatomic features of 1p/19q co-deletion and investigate the predictive values of tumor location and radiological characteristics for the survival of anaplastic oligodendroglial (AO) glioma patients. Voxel-based lesion-symptom mapping (VLSM) analysis was applied to define the brain regions associated with occurrence of 1p/19q co-deletion in a cohort of 206 AO tumor patients (discovery set) treated between May 2009 and September 2013. Retrospectively, the acquired clusters and radiological features were subjected to Kaplan-Meier survival analysis using data from the Chinese Glioma Genome Atlas (validation set) to evaluate their prognostic role in AO patients. The institutional review board approved this study. The right frontal lobe and right anterior insular lobe were specifically associated with high occurrence of 1p/19q co-deletion. For AO tumors not involving these areas, the absence of contrast enhancement predicted longer progression-free (p = 0.018) and overall survival (p = 0.020); moreover, in patients with contrast enhancement, edema could stratify the survival outcome (p = 0.013 for progression-free survival, p = 0.016 for overall survival). For AO tumors located in the VLSM-identified regions, edema was also able to stratify the survival outcome of patients without contrast enhancement (p = 0.025 for progression-free survival, p = 0.028 for overall survival). The 1p/19q co-deletion showed predilection for specific brain regions. According to the tumor involvement of VLSM-identified regions associated with 1p/19q co-deletion, radiological features were predictive for AO patient survival outcomes.

The Pluripotent Stem-Cell Marker Alkaline Phosphatase is Highly Expressed in Refractory Glioblastoma with DNA Hypomethylation

Hypomethylation of genomic DNA induces stem-cell properties in cancer cells and contributes to the treatment resistance of various malignancies. To examine the correlation between the methylation status of stem-cell-related genes and the treatment outcomes in patients with glioblastoma (GBM). The genome-wide DNA methylation status was determined using HumanMethylation450 BeadChips, and the methylation status was compared between a group of patients with good prognosis (survival > 4 yr) and a group with poor prognosis (survival < 1 yr). Immunohistochemistry for proteins translated from hypomethylated genes, including alkaline phosphatase (ALPL), CD133, and CD44, was performed in 70 GBMs and 60 oligodendroglial tumors. The genomic DNA in refractory GBM was more hypomethylated than in GBM from patients with relatively long survival (P = .0111). Stem-cell-related genes including ALPL, CD133, and CD44 were also significantly hypomethylated. A validation study using immunohistochemistry showed that DNA hypomethylation was strongly correlated with high protein expression of ALPL, CD133, and CD44. GBM patients with short survival showed high expression of these stem-cell markers. Multivariate analysis confirmed that co-expression of ALPL + CD133 or ALPL + CD44 was a strong predictor of short survival. Anaplastic oligodendroglial tumors without isocitrate dehydrogenase 1 mutation were significantly correlated with high ALPL expression and poor survival. Accumulation of stem-cell properties due to aberrant DNA hypomethylation is associated with the refractory nature of GBM.

1p/19q codeletion and RET rearrangements in small-cell lung cancer.

The prognosis of small-cell lung cancer (SCLC) is poor despite reports suggesting modest improvement in survival. To date, chemotherapy remains the cornerstone treatment for SCLC patients, and many studies have focused on identifying the molecular characteristics of SCLC, which serve as the basis for precision treatments that improve the prognosis of SCLC. For instance, the therapeutic effect of temozolomide, recommended for patients with relapsed SCLC, is linked to 1p/19q codeletion in anaplastic oligodendroglial tumors. A subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. In order to identify 1p/19q codeletion and RET rearrangement in SCLC patients, 32 SCLC resected specimens were retrospectively collected between 2008 and 2014 from the Zhejiang Cancer Hospital in People’s Republic of China. Fluorescence in situ hybridization was used to detect 1p/19q codeletion and RET rearrangement in the specimens. A 1p single deletion was detected in eight specimens, 19q single deletion was detected in three specimens, and only three specimens had a 1p/19q codeletion. None of the specimens had a RET rearrangement. The three patients whose specimens had a 1p/19q codeletion were alive after 58, 50, and 30 months of follow-up care. There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively). Our data showed that RET rearrangement may be not an ideal molecular target for SCLC therapies in People’s Republic of China. Instead, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC.

CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): Phase III Randomized Study of RT vs. RT+TMZ vs. TMZ for Newly Diagnosed 1p/19q-Codeleted Anaplastic Oligodendroglial Tumors. Analysis of Patients Treated on the Original Protocol Design (PL02.005)

CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): Phase III Randomized Study of RT vs. RT+TMZ vs. TMZ for Newly Diagnosed 1p/19q-Codeleted Anaplastic Oligodendroglial Tumors. Analysis of Patients Treated on the Original Protocol Design (PL02.005)

Pattern of Care of Anaplastic Oligodendroglioma and Oligoastrocytoma in a Korean Population: The Korean Radiation Oncology Group Study 13-12

This study investigated the treatment of anaplastic oligodendroglial tumors across nine Korean institutions. We reviewed the medical records from 381 patients with histologically confirmed anaplastic oligodentroglioma (AO) or anaplastic oligoastrocytoma (AOA) from 2000 to 2010. Clinical factors and treatment patterns were analyzed for each year. Post-operative therapy was performed in 354 patients (94.1%), of which 133 received radiation therapy (RT) alone and 189 received both RT and chemotherapy. RT alone was the preferred treatment toward the end of the study period (29.4% in 2000-2001 versus 56.3% in 2010, P=0.005). The use of procarbazine, lomustine, and vincristine (PCV) decreased (57.6% in 2000-2001 versus 28.6% in 2010, P=0.001) and the use of temozolomide (TMZ) increased (0% in 2000-2001 versus 61.9% in 2010, P<0.001) over the study period. A combination of chemotherapy and RT was used more often than RT alone in young patients (P=0.036) and patients with a good performance status (P=0.023). The 1p/19q co-deletion status and O-6-methyguanine-DNA methyltransferase methylation were analyzed since 2004 but were not significant factors for determining whether to administer chemotherapy. Among the patients who received chemotherapy, TMZ was used more often in patients with AOA (P=0.007) and PCV was used more often in patients with either multiple lesions (P=0.027) or the 1p/19q co-deletion (P=0.026). Our results demonstrate that the treatment pattern for oligodendroglial tumors changed significantly across the study period. In particular, TMZ has replaced PCV, and the use of molecular markers as well as RT alone has increased, but a unified protocol remains to be established.

Oligodendrogliomas: a short history of clinical developments.

*Brain Tumor Center at Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands; m.vandenbent@erasmusmc.nl oligodendroglioma: the early days Oligodendrogliomas have in particular attracted attention once it became clear that these are chemotherapy sensitive tumors. Although since the first description in 1926 and 1929 of oligodendroglial tumors it has been clear that these tumors are a special brand with a relatively good prognosis, they were taken for just another glioma subtype for many years thereafter [1]. Indeed, apart from a relatively more favorable prognosis of oligodendroglioma in comparison to their astrocytic counterparts and their often calcified lesions allowing a first diagnosis even at the time CT scans were not yet available, little pointed toward a specific significance for these tumors. This histological identification was somewhat complicated by the existence of another group with histological characteristics of both astrocytoma and oligodendroglioma, labeled mixed oligoastrocytoma. All these tumors were considered among the grade II and III glioma, and trials on grade II and high-grade glioma usually considered both astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Furthermore, trials on high-grade glioma usually lumped both grade III and grade IV (glioblastoma) under the heading ‘anaplastic glioma’. As a consequence, grade III tumors were in general treated as grade IV tumors, albeit with the clear notion their outcome was better. oligodendroglioma: the chemotherapy sensitive glioma This clinical significance of the diagnosis ‘oligodendroglioma’ radically changed when Cairncross et al. in 1988 and again in 1992 reported remarkably high response rates to procarbazine, CCNU (lomustine) and vincristine (PCV) chemotherapy in relapsing anaplastic oligodendroglioma [2]. This lead to confirmatory Phase II studies, and subsequently to studies in newly diagnosed anaplastic oligodendroglial tumors [3,4]. At that time, still no distinction was made between pure oligodendroglial tumors and mixed oligodendroglioma. At least in part driven by the wish not to miss oligodendroglial tumors the percentage of patients with oligodendroglioma showed a steep incline, from 5% of all glioma in historical series to no less than 20% of all glioma cases [5]. A clear change in diagnostic criteria was part of that increase, already pointing to the lack of objective criteria for the histological diagnosis of glioma in general but more in particular of oligodendroglial tumors.

Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas.

We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs). This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset. The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively). Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding.

A multicenter study of anaplastic oligodendroglioma: the Korean Radiation Oncology Group Study 13-12.

Although some existing evidence supports the addition of chemotherapy (CT) to radiation therapy (RT) for anaplastic oligodendroglioma treatment, controversy about both the criteria for suitable candidates and the optimal treatment schedule remains. We reviewed data from 376 newly diagnosed anaplastic oliogodendroglial tumor patients from nine Korean institutes were reviewed from 2000 to 2010. Total tumor removal was performed in 146 patients. More than 85% of the entire patients received postoperative RT, and 59% received CT. Approximately 50% (n = 189) received CT in addition to RT and 9% (n = 32) received CT only. A multivariate analysis revealed that younger age, frontal lobe location of the tumor, gross total removal, 1p/19q codeletion, and initial RT were associated with longer progression-free and overall survival rates. No difference was observed in outcomes from the treatment that included either temozolomide or PCV (procarbazine, lomustine, and vincristine) in addition to RT regardless of the 1p/19q deletion status. A clear improvement in progression-free and overall survival was observed for RT and combined CT/RT in compared with CT only. Postoperative RT appears to improve survival for entire group thus total removal and 1p/19q codeletion may not be sufficient criteria to omit RT as a treatment option. These results suggest that RT should continue to be offered as the standard treatment option for patients with anaplastic oligodendroglial tumors.

Input of molecular analysis in medical management of primary brain tumor patients

Primary brain tumors comprise a large group of malignant and non-malignant tumors including heterogeneous entities with various biological and clinical behaviors. Up till recently, diagnosis of brain cancers, that drives treatment decision-making, was based on integration of clinical, radiological and pathological features of patients and tumors. Over the last years, practical neuro-oncology has entered an era of molecular-based personalized medicine. Indeed, molecular features of tumors provide critical information to physicians for daily clinical management of patients and for design of relevant clinical research. Sporadic gliomas or glial tumors are the most common primary brain tumors in adults. Recently, their medical management has been revolutionized by molecular data. Indeed, optimal therapeutic management of grade III glioma patients now requires assessment of chromosome arms 1p/19q copy number and IDH mutational statuses as predictive and prognostic biomarkers. Indeed, two large phase III clinical trials have demonstrated that early chemotherapy plus radiotherapy, versus radiotherapy alone, doubles median overall survival of patients suffering from 1p/19q co-deleted and/or IDH mutated anaplastic oligodendroglial tumor. Interestingly, both biomarkers have been identified in a large proportion of WHO grade II gliomas. Their clinical value, in this population, is under investigation through multiple phase III clinical trials. In sporadic WHO grade I gliomas, and specifically in pilocytic astrocytomas, MAPK signaling pathway activation is a frequent event, mainly due to genetic alterations involving BRAF gene. This characteristic opens new therapeutic perspectives using MAPK signaling pathway inhibitors. Finally, in the most aggressive gliomas, WHO grade IV gliomas, two critical biomarkers have been identified: (i) MGMT promoter methylation associated with longer survival and better response to chemotherapy and (ii) IDH mutations predicting better prognosis. Although, further studies are needed, MGMT promoter methylation will undoubtedly be transferred soon to clinical practice. Molecular characteristics are beginning to be valuable and indispensable in neuro-oncology for better management of brain tumors patients. The near future will be marked by identification of novel molecular biomarkers and their validation for clinical practice.

Pattern of care of anaplastic oligodendroglioma and oligoastrocytoma in a Korean population: the Korean Radiation Oncology Group study 13-12.

This study investigated the treatment of anaplastic oligodendroglial tumors across nine Korean institutions. We reviewed the medical records from 381 patients with histologically confirmed anaplastic oligodendroglioma or anaplastic oligoastrocytoma (AOA) from 2000 to 2010. Clinical factors and treatment patterns were analyzed for each year. Post-operative therapy was performed in 354 patients (94.1 %), of which 133 received radiotherapy (RT) alone and 189 received both RT and chemotherapy. RT alone was the preferred treatment toward the end of the study period (29.4 % in 2000-2001 vs. 56.3 % in 2010, P = 0.005). The use of procarbazine, lomustine, and vincristine (PCV) decreased (57.6 % in 2000-2001 vs. 28.6 % in 2010, P = 0.001) and the use of temozolomide (TMZ) increased (0 % in 2000-2001 vs. 61.9 % in 2010, P < 0.001) over the study period. A combination of chemotherapy and RT was used more often than RT alone in young patients (P = 0.036) and patients with a good performance status (P = 0.023). The 1p/19q co-deletion status and O-6-methyguanine-DNA methyltransferase methylation were analyzed since 2004 but were not significant factors for determining whether to administer chemotherapy. Among the patients who received chemotherapy, TMZ was used more often in patients with AOA (P = 0.007) and PCV was used more often in patients with either multiple lesions (P = 0.027) or the 1p/19q co-deletion (P = 0.026). Our results demonstrate that the treatment pattern for oligodendroglial tumors changed significantly across the study period. In particular, TMZ has replaced PCV, and the use of molecular markers as well as RT alone has increased, but a unified protocol remains to be established.

NT-22 * PAV TREATMENT WITHOUT IMMEDIATE RADIOTHERAPY FOR ANAPLASTIC OLIGODENDROGLIAL TUMOR WITH 1p/19q CO-DELETION

OBJECTIVE: Recently, two randomized control trial, EORTC 26951 and RTOG 9402, has clarified that PCV + Radiation Therapy (RT) has survival benefit compared to in anaplastic oligodendroglial tumor and 1p/19q co-deleted tumor is a good prognosis factor. However, it is still unclear that RT is always necessary in both 1p/19q status tumor. MATERIAL AND METHODS: We retrospectively analyzed PFS and OS in thirty-three consecutive patients with anaplastic oligodendroglial tumor, who had been treated according to our treatment strategy. Briefly, in 1p/19q co-deleted case, only PAV chemotherapy is administrated after initial surgery without immediate RT. For recurrence, PAV or TMZ chemotherapy is considered after re-evacuation of local recurrence and definition of LOH status. In non-co-deleted case, immediate RT with TMZ or PAV is considered as a first-line therapy. RESULTS: With a median follow-up of 35.1 months, PFS and OS were 32.4 and 52.9 months, respectively, in all of our patients. In 1p/19q co-deleted tumor, PFS and OS were 58.8 months and N.R., which were significantly longer than those in non-co-deleted tumor, 10.2 and 27.3 months, respectively. CONCLUSION: In co-deleted cases, our data showed shorter PFS than two of Phase III trials (58.8 vs. 157 or 100.8 months). However OS was N.R. and no remarkable differences were found in PFS and OS of all of our cases compared to RT/PCV arms. It may suggest that tumors without RT are still sensitive to adjuvant chemotherapy after recurrence and such shorter-time recurrence would not influence on survival time in co-deleted cases.

GE-08 * TARGETED NEXT GENERATION SEQUENCING OF ARCHIVAL FFPE SAMPLES FROM EORTC STUDY 26951 SHOWS STRONG PROGNOSTIC VALUE OF A MOLECULAR CLASSIFICATION IN LOCALLY DIAGNOSED GRADE III OLIGODENDROGLIOMA

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.

GE-06 * PROGNOSTIC SIGNIFICANCE OF RELATIVE 1p19q CODELETION IN OLIGODENDROGLIAL TUMORS

BACKGROUND: 1p19q codeletion is a favorable prognostic marker for oligodendroglial tumors (OT) that in anaplastic OT is as well predictive of good response to radiotherapy and alkylator chemotherapy. OBJECTIVE: Assess outcome in relative 1p19q codeleted OT defined as the presence of both polysomy and 1p19q codeletion. METHODS: Between the years 2001-2013, 525 cases were examined at the University of Washington by dual color FISH for 1p or 19q deletion. 437 (82%) were WHO Grade 2 or 3 OT of which 209 (48%) were 1p19q codeleted. 72 (16%) were relatively deleted for either one or both 1p and 19q of which 28 (6%) were relatively 1p19q codeleted. RESULTS: Median overall survival was as follows. WHO Grade 2 OT (n = 296): 1p19q codeleted (n = 155) 13+ years; uni- or nondeleted (n = 86) 5+ years; relative deletion for one or both 1p19q (n = 41)) 6+ years; and relative 1p19q codeletion (n = 15) 6+ years. WHO Grade 3 OT (n = 168): 1p19q codeleted (n = 54) 11+ years; uni- or nondeleted (n = 70) 2.5 years; relative deletion for one or both 1p19q (n = 31)) 3 years; and relative 1p19q codeletion (n = 13) 4+ years. CONCLUSIONS: Median overall survival for OT either WHO Grade 2 or 3 with relative codeletion of 1p19q were approximately one half that of 1p19q codeleted tumors. The presence of relative codeletion, operationally defined as polysomy with deletions, is of prognostic significance.

BI-15 * RADIO- CHEMOTHERAPY IMPROVES SURVIVAL FOR IDH MUTANT, 1p19q-NON-CODELETED SECONDARY HIGH-GRADE-ASTROCYTOMA

OBJECTIVES: The RTOG 9402 trial reported an improved Outcome in IDH mutant and 1p19q-codeleted anaplastic oligodendroglial tumors after chemotherapy (CT) with radiotherapy (RT). We evaluated the efficacy of CT and RT in patients with IDH mutant, 1p19q-noncodeleted secondary high-grade astrocytoma (sHGA) WHO grades III and IV. PATIENTS AND METHODS: Treatment data from 109 patients with sHGA grades III and IV, developed from histologically confirmed low-grade astrocytoma grade II were retrospectively analyzed. IDH mutation-, 1p19q/codeletion- and MGMT-promoter methylation status were evaluable in all patients. Progression-free survival and overall survival (OS) in relation to adjuvant treatment modalities and molecular profiling were performed using the Kaplan-Meier method. RESULTS: Out of 109 patients, 88 patients (80.7%) harbored an IDH1 or 2 mutations, 30 patients a 1p19q-codeletion (27.5%), and 63 patients (57.8%) exhibited a methylated MGMT-promoter status. During the follow-up time 57 patients (52.2%) died. The postsurgical treatment for the 88 IDH mutant sHGA included: RT alone in 17 patients (19.3%), a combined RT and CT (RCT) in 48 patients (54.5%) and CT alone in 20 patients (22.7%). 3 patients did not receive any adjuvant treatment due to bad neurological conditions. At a median follow-up of 9.8 years, the median OS of all IDH mutant sHGA was 5.67 years (1.9-17.4 years). The OS in patients who received RCT was 6.4 years, which is significantly longer compared with those who underwent RT alone (1.2 years, hazard ratio 0.35, 95% CI 0.32-0.51. p = 0.011). After including only IDH mutant sHGA patients without a 1p19q-codeletion, the Kaplan-Meier curves estimates a significantly improved OS in the RCT cohort (33 patients) in comparison to patients who received RT alone (10 patients) (6.4 vs 1.2 years, hazard ratio 0.4, 95% CI 0.34-0.6, p = 0.022). CONCLUSIONS: Addition of alkylating-agent chemotherapy to radiation significantly improved overall survival in patients with IDH mutant and 1p19q-noncodeleted sHGA.