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Single-Institution Experience of Low-Grade Glioma Patient Outcomes Eligible for RTOG 9802
S90
International Journal of Radiation Oncology Biology Physics
203
Francisco, San Francisco, CA, 2First Affiliated Hospital of China Medical University, Shenyang, China, 3Harvard Medical School, Boston, MA
Single-Institution Experience of Low-Grade Glioma Patient Outcomes Eligible for RTOG 9802 C.R. Kreofsky,1 R.S. Youland,1 J.C. Buckner,2 J.H. Uhm,3 D.H. Lachance,3 and N.N. Laack1; 1Department of Radiation Oncology; Mayo Clinic, Rochester, MN, 2Division of Medical Oncology; Mayo Clinic, Rochester, MN, 3Department of Neuro-Oncology; Mayo Clinic, Rochester, MN Purpose/Objective(s): Long-term results of RTOG 9802 demonstrate a survival benefit for adjuvant (adj) chemotherapy (CT) vs radiotherapy (RT) alone in high-risk low grade glioma (LGG). While this study matured, clinical practice patterns continued to include observation following resection for these same patients. It is unknown if RT + CT yields a survival benefit compared to observation. As such, we compared outcomes of patients with high risk LGG, eligible for adj therapy on RTOG 9802 (age 40 years regardless of extent of resection, or age < 40 years with less than a gross total resection [GTR]), treated at a single institution during this era. Materials/Methods: Records from adults diagnosed with LGG between 1997 and 2008 were assessed. Patients were at least 18 years of age with a WHO grade II glioma confirmed by pathology review at our institution. Univariate and multivariate analysis (MVA) of prognostic factors were performed using JMP statistical software. Kaplan-Meier estimates were used to determine progression-free survival (PFS) and overall survival (OS) and compared using Log-rank test. Results: Tumor registry search returned 554 adults with LGG, of whom 276 met criteria for this analysis. The median age of all patients was 42 years; 157 patients 40 years at diagnosis and 119 patients <40 years with less than a GTR. The median follow-up was 6.2 years (0.1-18.1). Fifty-eight (21%), 101 (37%) and 117 (42%) patients had histology of astrocytoma (A), oligoastrocytoma (OA) and oligodendroglioma (O), respectively. Surgical resection was biopsy-only, subtotal resection (STR) and GTR in 135 (49%), 107 (39%), and 34 (12%) patients, respectively. Adj therapy, included observation in 81 (29%) patients, RT alone in 129 (47%) patients, RT + CT in 56 (20%) patients, and CT alone 10 (4%) patients. CT included: n Z 37 (57%) temozolomide, n Z 25 (38%) PCV, n Z 3 (5%) other. Median PFS was 3.5 years (2.9, 3.5 and 4.7 years for A, OA, and O, respectively, P Z 0.0008). Median PFS by adj therapy was 2.8, 4.1, 5.0, and 5.3 years for observation, RT alone, CT alone, and RT + CT, respectively, P Z 0.02). Median OS was 9.3 years (5.1, 8.8, and 14.1 years for A, OA, and O, respectively, P < 0.0001). Median OS by adj therapy was of 11.8, 8.1, 14.2, and 14.0 years for observation, RT alone, CT alone, and RT + CT, respectively, (P Z 0.08). MVA using histology, extent of resection, and adj therapy, demonstrated RT + CT was associated with an improved OS compared to RT alone (HR Z 0.59; 95% CI Z 0.37-0.91; P Z 0.02) but not compared to observation (HR Z 0.63; 95% CI Z 0.351.13; P Z 0.13). Observed patients were more likely to be O or OA histology or have a GTR (P Z 0.05 and P < 0.001, respectively). Conclusion: Our study shows similar patient characteristics and confirms outcomes to those patients enrolled on RTOG 9802. Adj RT + CT was associated with improved OS vs RT alone. RT + CT was not was not associated with statistically significant improvement in OS compared to initial observation. Observation may be a reasonable approach after resection for appropriately selected LGG. Author Disclosure: C.R. Kreofsky: None. R.S. Youland: None. J.C. Buckner: None. J.H. Uhm: None. D.H. Lachance: None. N.N. Laack: None.
204 Omission of Radiation Therapy for Low-Grade Gliomas: Molecular and Radiographic Correlates of Treatment Response and Disease Progression on a Phase 2 Clinical Trial of Adjuvant Temozolomide M. Wahl,1 J. Phillips,1 A. Molinaro,1 Y. Lin,1,2 A. Perry,1 D.A. HaasKogan,3 J. Costello,1 M. Dayal,1 N. Butowski,1 J. Clarke,1 M. Prados,1 M.S. Berger,1 S. Nelson,1 and S.M. Chang1; 1University of California, San
Purpose/Objective(s): Optimal adjuvant management of adult low grade gliomas (LGG) remains controversial, with adjuvant radiotherapy conferring improved survival outcomes at the cost of potential late toxicity. Previously presented results from a phase II clinical trial investigating the use of adjuvant temozolomide (TMZ) as an alternative to radiation in patients with LGG demonstrated progression-free survival (PFS) and overall survival (OS) comparable to historical controls receiving radiation alone. However, optimal candidates for omission of adjuvant radiation have not been established, and newly defined molecular subgroups may be crucial to appropriately risk stratify patients. Materials/Methods: One hundred twenty patients with newly diagnosed WHO grade II LGGs with gross residual disease after surgical resection were enrolled in a phase II clinical trial. Patients received monthly cycles of TMZ for up to 1 year or until disease progression, and were monitored with serial MRI prior to treatment and every 2 months during treatment. Ninety-seven patients with available tissue were grouped into molecular subtype based on 1p19q codeleton and IDH1 status (1p19q codel: 1p19q codeleted/IDH1-R132H mutated; IDH1mut: 1p19q intact/ IDH1-R132H mutated); IDH1wt: 1p19q intact/IDH1-R132H wild type). For 71 patients with available serial imaging, volumetric analysis was performed with tumor volume defined as the region of hyperintensity on fluid-attenuated inversion-recovery (FLAIR) imaging. Results: Tumor volume decreased significantly during the first 6 months of treatment for the entire cohort (28% median decrease, P < 0.001); volume was significantly decreased in 1p19q codel patients (32% decrease, P < 0.001), but not in IDH1mut (22% decrease, P Z 0.11) or IDH1wt (15% decrease, P Z 0.13). Molecular subtype was associated with the rate of disease progression during treatment (P < 0.001), PFS (P Z 0.007), and OS (P < 0.001). Pretreatment tumor volume was strongly associated with PFS and OS (P < 0.001). We identify a low-risk group of patients with 1p19q codeletion and pretreatment tumor volume 68 cm3 with a 0% risk of progression during treatment, median PFS of 4.9 years, and median OS not reached (95% lower CI, 10.8 years). Conclusion: We observe a significant decrease in tumor volume during treatment with TMZ specific to patients with 1p19q codeletion. Molecular subtype and pretreatment tumor volume are important predictive factors for PFS and OS in patients with newly diagnosed LGG receiving adjuvant TMZ. Patients with 1p19q codeletion and limited residual disease after surgery may thus be optimal candidates for omission of upfront adjuvant radiotherapy. Author Disclosure: M. Wahl: Employee; Illumina, Inc. Stock; Illumina, Inc. J. Phillips: None. A. Molinaro: None. Y. Lin: None. A. Perry: None. D.A. Haas-Kogan: None. J. Costello: None. M. Dayal: None. N. Butowski: None. J. Clarke: None. M. Prados: Honoraria; Actelion. Advisory; Actelion. M.S. Berger: None. S. Nelson: None. S.M. Chang: Advisory; Neonc Technologies.
205 Hippocampal Dosimetry Predicts for Cancer-Related Cognitive Impairment in Patients Treated With Cranial Radiation Therapy: Dosimetric Results of a Prospective Clinical Trial C. Okoukoni, E. McTyre, A.M. Peiffer, W. Hinson, R.E. Strowd, S. Rapp, and M.D. Chan; Wake Forest Baptist Medical Center, Winston-Salem, NC Purpose/Objective(s): Cancer-related cognitive impairment (CRCI) is relatively common after treatment of primary and metastatic brain tumors, however the temporality of cognitive decline after radiation therapy (RT) is not well defined, with reports of both early (<4 months) and late onset (>12 months) symptoms. Identifying dosimetric parameters predictive of CRCI is difficult due to the heterogeneity of patient characteristics, as well as inadequate documentation of confounding factors. Memory function is especially susceptible to radiation effect after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post-RT memory impairment.
International Journal of Radiation Oncology Biology Physics
203
Francisco, San Francisco, CA, 2First Affiliated Hospital of China Medical University, Shenyang, China, 3Harvard Medical School, Boston, MA
Single-Institution Experience of Low-Grade Glioma Patient Outcomes Eligible for RTOG 9802 C.R. Kreofsky,1 R.S. Youland,1 J.C. Buckner,2 J.H. Uhm,3 D.H. Lachance,3 and N.N. Laack1; 1Department of Radiation Oncology; Mayo Clinic, Rochester, MN, 2Division of Medical Oncology; Mayo Clinic, Rochester, MN, 3Department of Neuro-Oncology; Mayo Clinic, Rochester, MN Purpose/Objective(s): Long-term results of RTOG 9802 demonstrate a survival benefit for adjuvant (adj) chemotherapy (CT) vs radiotherapy (RT) alone in high-risk low grade glioma (LGG). While this study matured, clinical practice patterns continued to include observation following resection for these same patients. It is unknown if RT + CT yields a survival benefit compared to observation. As such, we compared outcomes of patients with high risk LGG, eligible for adj therapy on RTOG 9802 (age 40 years regardless of extent of resection, or age < 40 years with less than a gross total resection [GTR]), treated at a single institution during this era. Materials/Methods: Records from adults diagnosed with LGG between 1997 and 2008 were assessed. Patients were at least 18 years of age with a WHO grade II glioma confirmed by pathology review at our institution. Univariate and multivariate analysis (MVA) of prognostic factors were performed using JMP statistical software. Kaplan-Meier estimates were used to determine progression-free survival (PFS) and overall survival (OS) and compared using Log-rank test. Results: Tumor registry search returned 554 adults with LGG, of whom 276 met criteria for this analysis. The median age of all patients was 42 years; 157 patients 40 years at diagnosis and 119 patients <40 years with less than a GTR. The median follow-up was 6.2 years (0.1-18.1). Fifty-eight (21%), 101 (37%) and 117 (42%) patients had histology of astrocytoma (A), oligoastrocytoma (OA) and oligodendroglioma (O), respectively. Surgical resection was biopsy-only, subtotal resection (STR) and GTR in 135 (49%), 107 (39%), and 34 (12%) patients, respectively. Adj therapy, included observation in 81 (29%) patients, RT alone in 129 (47%) patients, RT + CT in 56 (20%) patients, and CT alone 10 (4%) patients. CT included: n Z 37 (57%) temozolomide, n Z 25 (38%) PCV, n Z 3 (5%) other. Median PFS was 3.5 years (2.9, 3.5 and 4.7 years for A, OA, and O, respectively, P Z 0.0008). Median PFS by adj therapy was 2.8, 4.1, 5.0, and 5.3 years for observation, RT alone, CT alone, and RT + CT, respectively, P Z 0.02). Median OS was 9.3 years (5.1, 8.8, and 14.1 years for A, OA, and O, respectively, P < 0.0001). Median OS by adj therapy was of 11.8, 8.1, 14.2, and 14.0 years for observation, RT alone, CT alone, and RT + CT, respectively, (P Z 0.08). MVA using histology, extent of resection, and adj therapy, demonstrated RT + CT was associated with an improved OS compared to RT alone (HR Z 0.59; 95% CI Z 0.37-0.91; P Z 0.02) but not compared to observation (HR Z 0.63; 95% CI Z 0.351.13; P Z 0.13). Observed patients were more likely to be O or OA histology or have a GTR (P Z 0.05 and P < 0.001, respectively). Conclusion: Our study shows similar patient characteristics and confirms outcomes to those patients enrolled on RTOG 9802. Adj RT + CT was associated with improved OS vs RT alone. RT + CT was not was not associated with statistically significant improvement in OS compared to initial observation. Observation may be a reasonable approach after resection for appropriately selected LGG. Author Disclosure: C.R. Kreofsky: None. R.S. Youland: None. J.C. Buckner: None. J.H. Uhm: None. D.H. Lachance: None. N.N. Laack: None.
204 Omission of Radiation Therapy for Low-Grade Gliomas: Molecular and Radiographic Correlates of Treatment Response and Disease Progression on a Phase 2 Clinical Trial of Adjuvant Temozolomide M. Wahl,1 J. Phillips,1 A. Molinaro,1 Y. Lin,1,2 A. Perry,1 D.A. HaasKogan,3 J. Costello,1 M. Dayal,1 N. Butowski,1 J. Clarke,1 M. Prados,1 M.S. Berger,1 S. Nelson,1 and S.M. Chang1; 1University of California, San
Purpose/Objective(s): Optimal adjuvant management of adult low grade gliomas (LGG) remains controversial, with adjuvant radiotherapy conferring improved survival outcomes at the cost of potential late toxicity. Previously presented results from a phase II clinical trial investigating the use of adjuvant temozolomide (TMZ) as an alternative to radiation in patients with LGG demonstrated progression-free survival (PFS) and overall survival (OS) comparable to historical controls receiving radiation alone. However, optimal candidates for omission of adjuvant radiation have not been established, and newly defined molecular subgroups may be crucial to appropriately risk stratify patients. Materials/Methods: One hundred twenty patients with newly diagnosed WHO grade II LGGs with gross residual disease after surgical resection were enrolled in a phase II clinical trial. Patients received monthly cycles of TMZ for up to 1 year or until disease progression, and were monitored with serial MRI prior to treatment and every 2 months during treatment. Ninety-seven patients with available tissue were grouped into molecular subtype based on 1p19q codeleton and IDH1 status (1p19q codel: 1p19q codeleted/IDH1-R132H mutated; IDH1mut: 1p19q intact/ IDH1-R132H mutated); IDH1wt: 1p19q intact/IDH1-R132H wild type). For 71 patients with available serial imaging, volumetric analysis was performed with tumor volume defined as the region of hyperintensity on fluid-attenuated inversion-recovery (FLAIR) imaging. Results: Tumor volume decreased significantly during the first 6 months of treatment for the entire cohort (28% median decrease, P < 0.001); volume was significantly decreased in 1p19q codel patients (32% decrease, P < 0.001), but not in IDH1mut (22% decrease, P Z 0.11) or IDH1wt (15% decrease, P Z 0.13). Molecular subtype was associated with the rate of disease progression during treatment (P < 0.001), PFS (P Z 0.007), and OS (P < 0.001). Pretreatment tumor volume was strongly associated with PFS and OS (P < 0.001). We identify a low-risk group of patients with 1p19q codeletion and pretreatment tumor volume 68 cm3 with a 0% risk of progression during treatment, median PFS of 4.9 years, and median OS not reached (95% lower CI, 10.8 years). Conclusion: We observe a significant decrease in tumor volume during treatment with TMZ specific to patients with 1p19q codeletion. Molecular subtype and pretreatment tumor volume are important predictive factors for PFS and OS in patients with newly diagnosed LGG receiving adjuvant TMZ. Patients with 1p19q codeletion and limited residual disease after surgery may thus be optimal candidates for omission of upfront adjuvant radiotherapy. Author Disclosure: M. Wahl: Employee; Illumina, Inc. Stock; Illumina, Inc. J. Phillips: None. A. Molinaro: None. Y. Lin: None. A. Perry: None. D.A. Haas-Kogan: None. J. Costello: None. M. Dayal: None. N. Butowski: None. J. Clarke: None. M. Prados: Honoraria; Actelion. Advisory; Actelion. M.S. Berger: None. S. Nelson: None. S.M. Chang: Advisory; Neonc Technologies.
205 Hippocampal Dosimetry Predicts for Cancer-Related Cognitive Impairment in Patients Treated With Cranial Radiation Therapy: Dosimetric Results of a Prospective Clinical Trial C. Okoukoni, E. McTyre, A.M. Peiffer, W. Hinson, R.E. Strowd, S. Rapp, and M.D. Chan; Wake Forest Baptist Medical Center, Winston-Salem, NC Purpose/Objective(s): Cancer-related cognitive impairment (CRCI) is relatively common after treatment of primary and metastatic brain tumors, however the temporality of cognitive decline after radiation therapy (RT) is not well defined, with reports of both early (<4 months) and late onset (>12 months) symptoms. Identifying dosimetric parameters predictive of CRCI is difficult due to the heterogeneity of patient characteristics, as well as inadequate documentation of confounding factors. Memory function is especially susceptible to radiation effect after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post-RT memory impairment.