Scheithauer, B. W.

e20519 Background: Radiation Therapy Oncology Group 9402 compared PCV chemotherapy plus radiation therapy (PCV+RT) versus RT alone for anaplastic oligodendroglioma. Here we report 1) longitudinal changes in cognition and quality of life, 2) effects of patient factors and treatments on cognition, quality of life and survival, and 3) prognostic implications of cognition and quality of life. Methods: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL) by repeat assessments. Scores were analyzed for survivors and within five years of death. Shared parameter models evaluated MMSE/B-QOL with survival. Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those dying within 5 years, MMSE scores were stable initially, while B-QOL scores decreased; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (P=0.0413 for MMSE; P=0.0016 for B-QOL) and were superior with age < 50 years (P<0.001 for MMSE; P=0.0554 for B-QOL) and KPS 80–100 (P<0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV+RT (HR=0.66, 95% CI=0.49–0.9, P=0.0084; HR=0.74, 95% CI=0.54–1.01, P=0.0592) in models with MMSE and B-QOL. There were no differences in MMSE and B-QOL scores between arms (P=0.4752 and P=0.2767, respectively); higher scores predicted longer survival. Conclusions: MMSE and B-QOL scores held steady in both arms for survivors. For those who died, B-QOL scores declined slowly until the last year of life, then rapidly. Younger, fitter patients had better MMSE and B-QOL scores and longer survival. No significant financial relationships to disclose.

Deletion (DL) of chromosome 1p is common in oligodendroglial (OLG) tumors and is prognostically significant. We studied 1p DL (FISH method) and morphologic/ultrastructural (EM)/immunohistochemical (IHC) features of OLG, in 22 tumors. Six of 12 gr II, 6 of 8 gr III and 1 of 2 gr IV tumors were 1p DL. On EM, all tumors contained round cells with lucent to organelle (Golgi, mitochondria, microtubules)‐rich cytoplasm and few or no intermediate filaments (IF); 3 features (myelin figures, whorls of IF, synapses) suggested OLG, astrocytic and neuronal status, respectively. OLG features were seen in 3 DL gr II OLG, 2 nondeleted (NDL) gr II and in 1 NDL gr III tumor. Astrocytic feature was seen in 2 DL gr II, 4 DL gr III, and in all 9 NDL tumors. Neuronal features were seen in 3 DL gr II OLG, 2 NDL gr II and in 1 NDL gr III tumor. Overall, the 3 phenotypes were present in 23 , 46 and 23 % in of DL OLGs and in 44, 100 and 33 % of NDL tumors, respectively. IHC for synaptophysin (SYN), neurofilament protein (NFP), chromogranin, and Neu N were performed. Reactivity(s) were noted in 77% of all tumors, 71% of pure OLG, 100% of mixed tumors, 69% of DL tumors, and 89% of NDL tumors. Neu‐N and SYN were most often seen. Of all tumors with OLG, astrocytic and/or neuronal EM, 86, 71 and 83% showed staining, respectively. In summary, a) ND is common in OLG, both pure and mixed, and b) OLG tumors with and without a glioneuronal EM +/− IHC phenotype may both be 1p DL. Mayo Clinic funded.

1521 Background: Gliomas are known to progress from low to high grade at relapse, but the frequency is not well understood. It is unclear whether survival of these pts differ as a function of histologic subtype, and as measured from initial diagnosis and from relapse; yet such pts are frequently combined in clinical trials. Methods: Central review of paired glioma tissues obtained at initial diagnosis (DX) and recurrence was performed in 208 pts enrolled in prospective NCCTG trials (recurrence ≤ 90 d excluded). Kaplan-Meier, log rank, ANOVA, and chi-square tests were utilized. Results: Relapse from low (1–2) to high grade (3–4) occurred in 18/42 (43%) oligodendrogliomas (oligo), 28/41 (68%) oligoastrocytomas (OA), and 14/20 (70%) astrocytomas (astro); p=0.031. There were differences in median OS (in yrs; 95% CI) from initial DX: oligo-7.5 (5.0, 12.6); OA-4.5 (3.8, 5.6); and astro-3.3(1.8, 5.1), p=0.002; and OS from high grade recurrence: oligo-2.1 (0.9,3.0); OA-1.0 (0.8,1.3); and astro-0.7 (1.8, 5.1); p=0.02. Median OS from initial DX (yrs, 95% CI) also differed between primary (initial DX) GBM-1.7 (1.5–2.2); secondary (at recurrence) GBM-3.7 (2.8, 4.2) and non-GBM (initial+recurrence)- 5.5, (4.9–7.0) respectively, p < 0.001. Mean time to recurrence (TTR), (yrs ± S.D.) also differed: 1.1±1.1; 2.9±1.8; and 4.0±2.9, respectively, p < 0.001; as did median OS from recurrence (yrs, 95% CI) [0.7 (0.5, 1.1); 0.6, (0.5, 1.0); and 1.6 (1.1, 2.1), respectively], p <0.001. OS differed between primary vs. secondary GBM from time of initial DX (p=0.041) and also from recurrence (p=0.017). Conclusions: Low grade astro and OA progressed to grade 3–4 more frequently than did pure oligo; these groups had significant differences in OS from initial diagnosis and from recurrence. There were significant differences in OS between pts with primary and secondary GBM from initial diagnosis and recurrence. These data have important implications in design of clinical trials. [Table: see text] No significant financial relationships to disclose.

1520 Background: Multiple variables may impact endpoints utilized to assess efficacy of investigational therapies for pts with recurrent gliomas. Understanding the nature of these variables should aid interpretation of results. Methods: 583 pts were enrolled to 15 consecutive recurrent glioma clinical trials conducted between 1980 and 2004. Identical patient, tumor, treatment and time variables were identified for each trial. Central neuropathology review was completed and pts were grouped by WHO diagnoses. Pts alive and progression-free at 6 months after start of treatment were a PFS6 ‘success’. Pts whose outcome was progression at first evaluation were classified as “Immediate Progression (ImmProg)”. Response was defined as regression, partial regression, or complete regression in the absence of worsening neurologic symptoms or increased corticosteroid dose. Univariable and multivariable Classification and Regression Trees (CART) models were used to identify factors associated with OS, PFS, PFS6, ImmProg, and Response. Results: Variables associated with outcomes for each endpoint assessed by CART models are shown in Table below. Conclusions: In clinical trials of recurrent glioma, age, PS, duration of disease, primary and recurrent histologic diagnosis, and primary and recurrent extent of resection are associated with outcomes. These variables should be validated in additional datasets for potential inclusion in reports of future clinical trials. [Table: see text] No significant financial relationships to disclose.

1502 Background: High-grade gliomas (HGG, WHO grades III-IV) are morphologically and genetically diverse, with survivals ranging from months to decades. Although WHO 2000 grading criteria are well established for pure astrocytomas [anaplastic astrocytoma (AA) and glioblastoma (GBM)], those for oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and oligodendroglioma (AO)] remain subjective, there being a debate regarding the existence of a grade IV variant based on the finding of necrosis, particularly with pseudopalisading (PPN). Methods: Overall survival of 916 adult (>20 yr) patients diagnosed between 1990 and 2005 with supratentorial HGG (77 AA, 481 GBM, 183 AOA, 175 AO) was analyzed by uni- (log-rank) and multivariate (Cox proportional hazards) models for significance of the following factors: microvascular proliferation, necrosis, patient age, surgery (stereotactic vs. open), location, primary vs. secondary tumor, year of diagnosis, and chromosome 1p and 19q losses by fluorescence in situ hybridization. Results: Necrosis was a statistically significant predictor of poor survival on multivariate analyses in AOA (P=0.035), but not in AO (log-rank P=0.048, Cox P=0.9), while PPN showed a trend towards significance on multivariate analysis only in AOA (P=0.096). Other independent predictors on multivariate analysis included age, grade, surgery type, and year of diagnosis for AA/GBM and age, primary tumor, and 1p/19q codeletion for both AOA and AO (P<0.05). Median survival for AOA patients whose tumors featured necrosis (20.7 mo) was significantly worse than their counterparts lacking necrosis (>104 mo); survival of the latter was more similar to that of AO (83.5 mo), whereas in the former it was better than GBM (10.5 mo) (log-rank P<0.0001). Conclusions: Stratification of oligoastrocytomas, but not of pure oligodendrogliomas, into grades III (AOA) and IV (GBM with oligodendroglial features) on the basis of necrosis is prognostically justified and is more accurate than the current approach of using a single anaplastic grade. These data provide impetus for the modification of present WHO criteria. No significant financial relationships to disclose.