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Stereotactic Radiation Therapy and the Management of Atypical Meningiomas: Outcomes in the Upfront and Recurrent Setting
S140
International Journal of Radiation Oncology Biology Physics
Author Disclosure: L. Rogers: None. P. Zhang: None. M.A. Vogelbaum: Consultant; Neuralstem, Inc., Pharmicokinesis, Inc. Chief Medical Officer and patent interests; Infuseon Therapeutics. Stock Options; Infuseon Therapeutics. Co-Chair; NRG. A. Perry: None. L. Ashby: Speaker’s Bureau; Novocure, Arbor Pharmaceuticals. J. Modi: None. A. Alleman: None. J.M. Galvin: None. D. Brachman: None. J.M. Jenrette: None. J. DeGroot: None. J.A. Bovi: None. M. Werner-Wasik: None. J.P. Knisely: None. M.P. Mehta: Research Grant; Novocure, Novellos. Consultant; BMS, Celldex, Elekta, Novartis, Novocure, Roche. Stock Options; Pharmacyclics, Board of Directors. Chair; NRG.
Purpose/Objective(s): Genomic analyses of low-grade glioma (LGG) are leading to diagnostic and prognostic classification according to IDH mutation and 1p/19q co-deletion status, with patients harboring both alterations enjoying the best prognosis and those whose tumors are driven by other genomic aberrations having survival more comparable to glioblastoma (GBM). We previously used The Cancer Genome Atlas (TCGA) GBM expression profile database to identify a 12-gene set prognostic for survival in GBM. This study aimed to determine whether this gene expression profile may also distinguish favorable and unfavorable subgroups in LGG. Materials/Methods: Publicly available clinical and gene expression data from 459 grade 2 or 3 astrocytoma, oligodendroglioma, and mixed oligoastrocytoma samples were downloaded from the TCGA data portal. Gene expression data were log2 transformed and used to calculate a meta-gene score, utilizing weighting coefficients derived in our previous modeling of GBM survival (IJROBP 90(1):S38-S39, 2014). Copy number SNP array data were used to assess for 1p/19q co-deletion and sequencing data were used to identify patients with IDH mutations. For survival analysis, patients were stratified into 3 molecular subclasses according to IDH mutation and 1p/19q co-deletion status (IDH mutant + 1p/19q co-deleted; IDH mutant + 1p/19q intact; IDH wild-type), and into favorable (lowest 25%) and unfavorable (highest 75%) meta-gene score groups. Results: Among all patients with LGG, median OS differed significantly between patients with favorable versus unfavorable meta-gene scores based on our 12-gene set (7.3 vs. 10.9 yrs, P Z 0.04). The meta-gene score retained prognostic significance in a Cox regression model with age and histopathologic tumor grade as covariates (P Z .0005), but fell out of the model when the molecular subclass was entered. The meta-gene score was not associated with survival within IDH-mutant LGG, but trended towards significance within IDH wild-type LGG (P Z .14, n Z 86). Of 86 IDH wild-type LGGs in the TCGA database, 77 (89.5%) had unfavorable metagene scores. Of these 77 patients, 34 (44%) died during follow-up, while only 1 of 9 patients (11%) with IDH wild-type LGG and a favorable metagene score died in available follow-up. Conclusion: A 12-gene expression signature derived from analysis of the TCGA GBM database was also found to have prognostic value among lower grade gliomas. IDH wild-type patients were more likely to have unfavorable meta-gene scores, consistent with the hypothesis that IDH wild-type LGG may behave more similarly to GBM than other molecular subclasses. As in GBM, unfavorable meta-gene scores were associated with poor clinical outcomes in IDH wild-type LGG. Author Disclosure: B. Huff: None. I.R. Crocker: None. W.J. Curran: Group Chair; NRG Oncology. H. Shu: None.
318 Stereotactic Radiation Therapy and the Management of Atypical Meningiomas: Outcomes in the Upfront and Recurrent Setting H.P. Bagshaw, R.L. Jensen, C.A. Palmer, and D.C. Shrieve; University of Utah Huntsman Cancer Institute, Salt Lake City, UT Purpose/Objective(s): To evaluate outcomes in patients with atypical meningiomas treated with surgery alone compared to surgery and radiation therapy in the upfront and recurrent settings. Materials/Methods: Cases of pathologically confirmed atypical meningioma treated from 1991 to 2014 at our institution were retrospectively reviewed. Local control and overall survival were assessed. Comparison was made for patients receiving radiation therapy as part of initial treatment and treatment at first recurrence. Kaplan-Meier and log-rank test for significance were used for local control and survival analyses. Results: Sixty-one patients with 65 tumors met inclusion criteria. The initial therapy for 68% (44/65) was surgery alone, 32% (21/65) underwent surgery and radiation therapy. Of those patients treated with radiation, 18 received stereotactic fractionated radiation therapy and 3 received stereotactic radiosurgery. At a median follow-up of 41 months, 53 patients were alive. The crude local control was 58% (38/65) with a median time to local failure of 50 months. Seventy-six percent (16/21) of tumors treated with upfront surgery and radiation therapy were controlled with a median time to local failure of 180 months, compared to 50% (22/44) of tumors treated with surgery alone being controlled with a median time to local failure of 46 months (P Z .0388). Gross total resection was obtained in 71% (46/65) of tumors, and of these, 100% (10/10) treated with adjuvant radiation therapy were controlled, compared to 58% (21/36) of tumors treated with gross total resection alone (P Z 0.0163). Eighty-eight percent of tumors (7/8) failed following subtotal resection alone, compared to 45% (5/11) local failure rate with subtotal resection and adjuvant radiation therapy. Twenty-seven tumors were identified that failed initial treatment, and 74% (20/27) of these failed salvage therapy with a median time to local failure of 26 months. Failures following initial therapy were difficult to control irrespective of the salvage treatment modality. Conclusion: Historically, gross total resection has been thought to be the most important intervention for patients with atypical meningioma. The findings presented here suggest that the addition of adjuvant radiation therapy following GTR confers a local control benefit. It is also apparent that recurrent disease is difficult to control, emphasizing the importance of aggressive initial treatment. Author Disclosure: H.P. Bagshaw: None. R.L. Jensen: Consultant; Varian, Medtronic. Board Member; Pharmokokinesis. C.A. Palmer: None. D.C. Shrieve: Trustee for the American Board of Radiology; American Board of Radiology. Consultant regarding technology for radiosurgery treatments of brain metastases; BrainLab AG.
319 Evaluation of the Prognostic Performance of a 12-gene Glioblastoma Signature Among Low-Grade Glioma Patients in the Cancer Genome Atlas Database B. Huff,1,2 I.R. Crocker,1,3 W.J. Curran, Jr,1,3 and H.K.G. Shu1,4; 1Atlanta, GA, 2Winship Cancer Institute of Emory University, Atlanta, GA, 3Winship Cancer Institute, Emory University, Atlanta, GA, 4The Winship Cancer Institute, Emory University, Atlanta, GA
320 Somatic Mutation-Based Biomarkers Identify a Poor Prognostic Subgroup in Grade 3 Gliomas Z. Wardak, S. Park, T.H. Hwang, and K.S. Choe; University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): Grade 3 gliomas constitute a heterogeneous population with variable clinical outcomes and no consensus on therapeutic approach. Tailored therapy based on prognosis would be optimal, but currently established prognostic factors are often not reliable. The hypothesis was that analysis of gene expression profiles may identify subgroups within grade 3 gliomas with distinct clinical outcomes, which may guide the intensity of therapy. Materials/Methods: We previously generated a glioma-specific molecular signature, which consists of 39 genes commonly mutated and thought implicated in gliomagenesis. The Cancer Genome Atlas (TCGA) database was evaluated to identify 176 grade 3 glioma patients with RNA-sequence data. The median age was 45 (range, 22e75), 70% were male, and 67% had a Karnofsky Performance Status (KPS) >Z 90. Radiation (RT) and chemotherapy were administered to 72% and 65%, respectively. Sixtyeight grade 3 gliomas from The Repository for Molecular Brain Neoplasia Data (REMBRANDT) were used for independent validation.
International Journal of Radiation Oncology Biology Physics
Author Disclosure: L. Rogers: None. P. Zhang: None. M.A. Vogelbaum: Consultant; Neuralstem, Inc., Pharmicokinesis, Inc. Chief Medical Officer and patent interests; Infuseon Therapeutics. Stock Options; Infuseon Therapeutics. Co-Chair; NRG. A. Perry: None. L. Ashby: Speaker’s Bureau; Novocure, Arbor Pharmaceuticals. J. Modi: None. A. Alleman: None. J.M. Galvin: None. D. Brachman: None. J.M. Jenrette: None. J. DeGroot: None. J.A. Bovi: None. M. Werner-Wasik: None. J.P. Knisely: None. M.P. Mehta: Research Grant; Novocure, Novellos. Consultant; BMS, Celldex, Elekta, Novartis, Novocure, Roche. Stock Options; Pharmacyclics, Board of Directors. Chair; NRG.
Purpose/Objective(s): Genomic analyses of low-grade glioma (LGG) are leading to diagnostic and prognostic classification according to IDH mutation and 1p/19q co-deletion status, with patients harboring both alterations enjoying the best prognosis and those whose tumors are driven by other genomic aberrations having survival more comparable to glioblastoma (GBM). We previously used The Cancer Genome Atlas (TCGA) GBM expression profile database to identify a 12-gene set prognostic for survival in GBM. This study aimed to determine whether this gene expression profile may also distinguish favorable and unfavorable subgroups in LGG. Materials/Methods: Publicly available clinical and gene expression data from 459 grade 2 or 3 astrocytoma, oligodendroglioma, and mixed oligoastrocytoma samples were downloaded from the TCGA data portal. Gene expression data were log2 transformed and used to calculate a meta-gene score, utilizing weighting coefficients derived in our previous modeling of GBM survival (IJROBP 90(1):S38-S39, 2014). Copy number SNP array data were used to assess for 1p/19q co-deletion and sequencing data were used to identify patients with IDH mutations. For survival analysis, patients were stratified into 3 molecular subclasses according to IDH mutation and 1p/19q co-deletion status (IDH mutant + 1p/19q co-deleted; IDH mutant + 1p/19q intact; IDH wild-type), and into favorable (lowest 25%) and unfavorable (highest 75%) meta-gene score groups. Results: Among all patients with LGG, median OS differed significantly between patients with favorable versus unfavorable meta-gene scores based on our 12-gene set (7.3 vs. 10.9 yrs, P Z 0.04). The meta-gene score retained prognostic significance in a Cox regression model with age and histopathologic tumor grade as covariates (P Z .0005), but fell out of the model when the molecular subclass was entered. The meta-gene score was not associated with survival within IDH-mutant LGG, but trended towards significance within IDH wild-type LGG (P Z .14, n Z 86). Of 86 IDH wild-type LGGs in the TCGA database, 77 (89.5%) had unfavorable metagene scores. Of these 77 patients, 34 (44%) died during follow-up, while only 1 of 9 patients (11%) with IDH wild-type LGG and a favorable metagene score died in available follow-up. Conclusion: A 12-gene expression signature derived from analysis of the TCGA GBM database was also found to have prognostic value among lower grade gliomas. IDH wild-type patients were more likely to have unfavorable meta-gene scores, consistent with the hypothesis that IDH wild-type LGG may behave more similarly to GBM than other molecular subclasses. As in GBM, unfavorable meta-gene scores were associated with poor clinical outcomes in IDH wild-type LGG. Author Disclosure: B. Huff: None. I.R. Crocker: None. W.J. Curran: Group Chair; NRG Oncology. H. Shu: None.
318 Stereotactic Radiation Therapy and the Management of Atypical Meningiomas: Outcomes in the Upfront and Recurrent Setting H.P. Bagshaw, R.L. Jensen, C.A. Palmer, and D.C. Shrieve; University of Utah Huntsman Cancer Institute, Salt Lake City, UT Purpose/Objective(s): To evaluate outcomes in patients with atypical meningiomas treated with surgery alone compared to surgery and radiation therapy in the upfront and recurrent settings. Materials/Methods: Cases of pathologically confirmed atypical meningioma treated from 1991 to 2014 at our institution were retrospectively reviewed. Local control and overall survival were assessed. Comparison was made for patients receiving radiation therapy as part of initial treatment and treatment at first recurrence. Kaplan-Meier and log-rank test for significance were used for local control and survival analyses. Results: Sixty-one patients with 65 tumors met inclusion criteria. The initial therapy for 68% (44/65) was surgery alone, 32% (21/65) underwent surgery and radiation therapy. Of those patients treated with radiation, 18 received stereotactic fractionated radiation therapy and 3 received stereotactic radiosurgery. At a median follow-up of 41 months, 53 patients were alive. The crude local control was 58% (38/65) with a median time to local failure of 50 months. Seventy-six percent (16/21) of tumors treated with upfront surgery and radiation therapy were controlled with a median time to local failure of 180 months, compared to 50% (22/44) of tumors treated with surgery alone being controlled with a median time to local failure of 46 months (P Z .0388). Gross total resection was obtained in 71% (46/65) of tumors, and of these, 100% (10/10) treated with adjuvant radiation therapy were controlled, compared to 58% (21/36) of tumors treated with gross total resection alone (P Z 0.0163). Eighty-eight percent of tumors (7/8) failed following subtotal resection alone, compared to 45% (5/11) local failure rate with subtotal resection and adjuvant radiation therapy. Twenty-seven tumors were identified that failed initial treatment, and 74% (20/27) of these failed salvage therapy with a median time to local failure of 26 months. Failures following initial therapy were difficult to control irrespective of the salvage treatment modality. Conclusion: Historically, gross total resection has been thought to be the most important intervention for patients with atypical meningioma. The findings presented here suggest that the addition of adjuvant radiation therapy following GTR confers a local control benefit. It is also apparent that recurrent disease is difficult to control, emphasizing the importance of aggressive initial treatment. Author Disclosure: H.P. Bagshaw: None. R.L. Jensen: Consultant; Varian, Medtronic. Board Member; Pharmokokinesis. C.A. Palmer: None. D.C. Shrieve: Trustee for the American Board of Radiology; American Board of Radiology. Consultant regarding technology for radiosurgery treatments of brain metastases; BrainLab AG.
319 Evaluation of the Prognostic Performance of a 12-gene Glioblastoma Signature Among Low-Grade Glioma Patients in the Cancer Genome Atlas Database B. Huff,1,2 I.R. Crocker,1,3 W.J. Curran, Jr,1,3 and H.K.G. Shu1,4; 1Atlanta, GA, 2Winship Cancer Institute of Emory University, Atlanta, GA, 3Winship Cancer Institute, Emory University, Atlanta, GA, 4The Winship Cancer Institute, Emory University, Atlanta, GA
320 Somatic Mutation-Based Biomarkers Identify a Poor Prognostic Subgroup in Grade 3 Gliomas Z. Wardak, S. Park, T.H. Hwang, and K.S. Choe; University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): Grade 3 gliomas constitute a heterogeneous population with variable clinical outcomes and no consensus on therapeutic approach. Tailored therapy based on prognosis would be optimal, but currently established prognostic factors are often not reliable. The hypothesis was that analysis of gene expression profiles may identify subgroups within grade 3 gliomas with distinct clinical outcomes, which may guide the intensity of therapy. Materials/Methods: We previously generated a glioma-specific molecular signature, which consists of 39 genes commonly mutated and thought implicated in gliomagenesis. The Cancer Genome Atlas (TCGA) database was evaluated to identify 176 grade 3 glioma patients with RNA-sequence data. The median age was 45 (range, 22e75), 70% were male, and 67% had a Karnofsky Performance Status (KPS) >Z 90. Radiation (RT) and chemotherapy were administered to 72% and 65%, respectively. Sixtyeight grade 3 gliomas from The Repository for Molecular Brain Neoplasia Data (REMBRANDT) were used for independent validation.