Hypofractionated Stereotactic Radiation Therapy Following Surgical Resection for Brain Metastases: A Retrospective Analysis of 95 Patients

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International Journal of Radiation Oncology  Biology  Physics

better understanding of the pathways involved in chordomas radioresistance should give rise to new-targeted therapies. Author Disclosure: H. Mammar: None. M. Polivka: None. Y. Belkacemi: None. G. Lot: None. S. Froelich: None. A. Carpentier: None. S. Clemenceau: None. S. Gaillard: None. P. Paquis: None. I. BirtwislePeyrottes: None. F. Burel-Vandenbos: None. K. Mokhtari: None. K. Kerrou: None. J. Talbot: None. R. Dendale: None. P. Bondiau: None. J. Pouyssegur: None. N. Mazure: None.

However, because these indices were validated to estimate survival only at the time of initial diagnosis of brain metastases, it is unclear whether or not they remain prognostic when used months after the discovery of brain metastases. In this study, we assess these prognostic indices in patients evaluated for SRS delayed from their initial diagnosis. Materials/Methods: We reviewed all patients treated at our institution with SRS for brain metastases from 2009 to 2014. One hundred twenty-one patients had all information available to construct scores for the following prognostic indices: Score Index for Radiosurgery (SIR), Basic Score for Brain Metastases (BSBM), RTOG Recursive Partitioning Analysis (RPA), Graded Prognostic Assessment (GPA), and Disease-Specific Graded Prognostic Assessment (DS-GPA). Of these, we identified and analyzed 72 patients who underwent SRS more than 1 month from their initial diagnosis. Median time from diagnosis of brain metastasis to SRS was 2.9 months (range 1- 82). Survival was defined by time from treatment to death. In cases where prognostic indexes had more than 3 scores, we categorized the scores into 3 groups within each index according to similar survival. Kaplan-Meier survival curves were constructed for each group and underwent a pairwise comparison within each index. The Tarone-Ware test was used to account for non-proportionality. Results: Median patient age and KPS at time of SRS were 60 years (range 25 -90) and 80 (range 50-100), respectively. Median interval between SRS to last contact was 6.7 months (range 0.2-35.6). A median of 2 tumors were treated per treatment course (range 1-5) with a median dose of 18 Gy (range 13-24 Gy). The median survival was 9 months with 6- and 12-month survival rates of 64% and 31%, respectively. The DS-GPA was the only index to have statistically significant p-values between each scores survival curve. Pvalues between group 1 vs 2, 1 vs 3, and 2 vs 3 were 0.002, <0.001, and 0.045.

2228 A Novel Approach to Diffusion Weighted Imaging Analysis in Newly Diagnosed GBM Y. Zhuge,1 H. Ning,1 J.Y. Cheng,1 R.S. Kirkland,2 B. Arora,1 R.W. Miller,1 A. Kaushal,1 K.A. Camphausen,1 and A.V. Krauze1; 1National Cancer Institute, National Institutes of Health, Bethesda, MD, 2University of Missouri, Columbia, MO Purpose/Objective(s): Conventional MRI is no longer sufficient to accurately identify tumor presence considering the widely documented infiltrative nature of gliomas. Diffusion Weighted Imaging (DWI) has lent further interpretation to available imaging, but data on the optimal combination of DWI sequences to be employed remains elusive. Our intent was to use a convolutional neural network approach to machine learning employing DWI sequences (apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV)) to identify an imaging biomarker for GBM. Materials/Methods: Ten histologically documented GBM cases with available detailed operative reports and gross tumor present on DWI prior to the administration of radiation therapy were selected. T1 post-gad images were used to manually delineate tumor which were then coregistered with DWI series. These 10 manually delineated tumors were used to train a convolutional neural network classifier (CNN). In testing, the trained CNN is employed to assign each pixel in the image a probability of belonging to tumor. Receiver Operating Characteristic (ROC) analysis was performed on the probability map to determine optimum thresholds for tumor grading and to obtain the sensitivity, specificity, and positive and negative predictive values for identifying high-grade gliomas. Results: Backtesting of the 10 GBM cases used for machine training achieved almost 100% probability concordance with the T1-gad manually delineated tumors. The trained CNN was then tested on 5 GBM patient datasets with T1-gad, ADC, rCBV images. A sensitivity of 75% and a specificity of 80% with positive and negative predictive values of 79% and 76% respectively were achieved. Optimum threshold for tumor was 0.47. Conclusion: The convolutional neural network approach to DWI analysis may be very useful in identifying a high grade glioma imaging biomarker. Further training with patient data will further improve the accuracy of this approach, enabling its use for recurrence pattern analysis in setting of radiation therapy and systemic treatment, with possible future applicability in tumor grading as well as radiation treatment field design. Author Disclosure: Y. Zhuge: None. H. Ning: None. J.Y. Cheng: None. R.S. Kirkland: None. B. Arora: None. R.W. Miller: None. A. Kaushal: None. K.A. Camphausen: None. A.V. Krauze: None.

2229 Using Prognostic Indices for Brain Metastases in the Setting of Delayed Stereotactic Radiosurgery (SRS) T. Malouff,1 N.R. Bennion,2 V. Verma,3 G.A. Martinez,4 N. Balkman,4 A.R. Bhirud,3 and C. Lin3; 1Creighton University, School of Medicine, Omaha, NE, 2University of Nebraska Medical Center, Omaha, NE, 3 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, 4Brigham Young University, Provo, UT Purpose/Objective(s): SRS is an important tool in treating brain metastases and has made modern treatment options more sophisticated. Some patients may benefit from radiosurgery at the initial diagnosis of brain metastasis while others may benefit from delayed SRS after the use of whole brain radiation (WBRT) or surgery. Prognostic scoring systems help select patients who will benefit from SRS by estimating their survival.

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p-values for pairwise comparisons

Index

Group 1 vs 2

Group 2 vs 3

Group 1 vs 3

SIR BSBM RPA GPA DS-GPA

0.027 0.79 0.005 0.001 0.10

0.421 <0.007 0.187 0.359 0.23

0.041 <0.001 0.001 0.003 <0.001

Conclusion: Prognostic indices remain important tools in the delayed setting of SRS though our findings warrant more careful index selection and interpretation. Author Disclosure: T. Malouff: None. N.R. Bennion: None. V. Verma: None. G.A. Martinez: None. N. Balkman: None. A.R. Bhirud: None. C. Lin: None.

2230 Hypofractionated Stereotactic Radiation Therapy Following Surgical Resection for Brain Metastases: A Retrospective Analysis of 95 Patients M. Dore,1 L. Campion,2 G. Delpon,3 F. Thillays,4 and S.A. Martin5; 1ICO Rene Gauducheau, Department of Radiation Oncology, Saint Herblain, France, 2ICO Rene Gauducheau, Department of Statistic, Saint Herblain, France, 3ICO, Nantes Saint Herblain, France, 4Department of Radiation Oncology, ICO, Nantes Saint Herblain, France, 5CHU Nantes, department of neurosurgery, Nantes, France Purpose/Objective(s): To evaluate local control after surgical resection and NovalisÒ hypofractionated stereotactic radiation therapy (HFSRS) to postoperative resection cavities in patients with brain metastases. Materials/Methods: We retrospectively reviewed patients treated by HFSRS (7.7 Gy * 3 prescribed to the 70% isodose line) following resection for brain metastases from March 2008 to January 2014, excluding prior radiation therapy. PTV was the resection cavity with the inclusion of a 2mm margin. Graded Prognostic Assessment score (GPA) and Recursive Partitioning Analysis score (RPA) were reviewed. MRI was done before HFSRS and every 3 months after. The primary endpoint was local failure (recurrence within surgical cavity). Secondary endpoints were distant failure rates (intracranial metastasis outside of treated volume including

Volume 93  Number 3S  Supplement 2015 leptomeningeal disease) and radionecrosis occurrence (confirmed by histology after resection). Local and distant failures were estimated using the Kaplan-Meier method. Interests groups were compared by Log rank test at the univariate step. Multivariate analysis was performed using Cox model. Results: A total of 95 patients (97 lesions) were available for analysis. Two of them had two metastasis resected together. Non-small cell lung cancer histology (NSCLC) represented 39.2%. The most represented GPA score was 3 (48%), and RPA score was 2 (57%). Median initial tumor volume was 11.4 cc (range, 1.0-67.2 cc) and median PTV was 12.9 cc (range, 0.8-64.7 cc). The median follow-up was 17 months (range, 0.6 - 76 months). The 6-month, 1-year and 2-year local control rates were 91%, 84% and 83%, respectively. Factors associated with improved local control were initial tumor volume < 9.5 cc (pZ0.05), no cavity MRI enhancement before radiation (p< 0.00001), PTV < 12cc (pZ0.005) and GPA score  2 (pZ0.009). The 6-months, 1-year and 2-year distant cerebral control rates were 70%, 56% and 39%, respectively. No factors were predictive of distant failure. Leptomeningeal progression was noted in 28% of distant failure. Tumor location (supratentorial vs infratentorial) and meningeal contact were not significantly associated with the occurrence of leptomeningeal disease. Thirty-three percent of patients received whole brain radiation therapy (WBRT) and the median time after HFSRS was 204 days (range, 12-1366). The median survival time was 25 months (95% CI, 15.6-34.7 months). Brain radionecrosis occurred in 7%. Conclusion: Adjuvant multidose SRS to the post-operative cavity in patients with brain metastases results in excellent local control, especially for selected patients with PTV < 12 cc, no cavity contrast enhancement on MRI and GPA score  2. It defers the use of whole-brain radiation with a low rate of brain radionecrosis. Author Disclosure: M. Dore: None. L. Campion: None. G. Delpon: None. F. Thillays: None. S. Martin: None.

2231 Predictors of Individual Tumor Local Control After Stereotactic Radiosurgery (SRS) for Melanoma Brain Metastases in the Era of Biologic Therapy S. Acharya,1 C.D. Abraham,2 R. Dryzmala,3 D. Yang,4 T.A. DeWees,4 C.I. Tsien,3 and J. Huang5; 1Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 2Washington University, St. Louis, MO, 3Washington University, Saint Louis, MO, 4 Washington University School of Medicine, St. Louis, MO, 5Washington University, St. Louis, MO Purpose/Objective(s): Biologic therapies such as BRAF inhibitors and ipilimumab have been shown to improve systematic control of metastatic melanoma; however, their impact on local control of brain metastases is unclear. We aim to identify predictors of individual tumor local control after SRS in the era of biologic therapy, taking into account dosimetric parameters that have been predictive of local control in other histologies. Materials/Methods: Between October 2005 and May 2014, a total of 150 melanoma brain metastases from 54 patients were treated with single fraction SRS. Repeat SRS to the same lesion and post-operative cases were excluded. Local failure was defined as an increase in lesion size on MRI after SRS. Sixteen patients (65 metastases) received BRAF inhibitors (vermurafenib or dabrafenib) prior to and/or after SRS. Fourteen patients (45 metastases) received ipilimumab prior to and/or after SRS. Prognostic factors were evaluated using Kaplan Meier product-limit method and Cox proportional hazards regression model. Cumulative incidence of local failure (LF) was calculated using a competing risks model and compared using Gray’s test. Results: Median follow up was 7.8 months, and median overall survival (OS) after SRS was 8.1 months. Median age was 56 (range: 31-78) and median KPS was 90 (range: 70-100). Median tumor volume was 0.42 cc (range: 0.01 e 23.7 cc) and median prescription dose was 20 Gy (range 11.2 e 24 Gy). The cumulative incidence of local failure at 6 and 12 months was 15% (95% CI: 10% e 21%) and 21.5% (95% CI: 15.5% e28.2%) respectively. There was no significant difference in LF between those who received BRAF inhibitors and those who did not (6 month LF: 13.5% vs 7.2%, pZ0.38 Gray’s test) and between those who received ipilimumab and those who did not (6 month LF: 20% vs. 14%, pZ0.268 Gray’s test). On univariate analysis, the variables predictive of LF included larger tumor volume (pZ0.015), female gender

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(pZ0.011) and smaller volume of tumor receiving 18 Gy (V18) through 37 Gy (V37) (p-values ranging from 0.001 to 0.047). V32 was chosen for the multivariate model based on prior data (Abraham, SNO 2014). On multivariate analysis, lower V32 (Hazard Ratio [HR]: 0.14, 95% Confidence interval [CI]: 0.04 e 0.58, pZ0.006) and female gender (HR: 2.76, 95% CI: 1.33 e 5.72, pZ0.006) remained independently predictive of LF. The only predictor of OS was total volume of intracranial disease at initial SRS presentation (HR: 1.06, 95% CI: 1.02 e 1.11). Radiation necrosis, as diagnosed on MRI, developed in 5.3% (8/150) of metastases. Conclusion: BRAF inhibitor and ipilimumab do not appear to significantly improve tumor local control when treated with SRS. Attention should be paid to maintaining hot spots such as V32 when planning SRS cases for melanoma. Author Disclosure: S. Acharya: None. C.D. Abraham: None. R. Dryzmala: None. D. Yang: None. T.A. DeWees: None. C.I. Tsien: None. J. Huang: None.

2232 Functional Profiling of a Glioblastoma (GBM) Patient-Derived Cell Line (PDCL) Panel Identifies Cell-Intrinsic Differential Radiation Response That Correlates With TP53 Mutations M.A. Huynh,1 C.L. Maire,2 M. Abazeed,3 D. Adams,4 K. Pelton,2 N. Pinnell,2 S. Ramkissoon,5 H. Korideck,2 P. Van Hummelen,2 A. Thorner,2 P. Wen,6 A.H. Ligon,5 S. Schreiber,7 M. Meyerson,2,4 K.L. Ligon,5 and B.M. Alexander6; 1Dana-Farber/Brigham & Women’s Cancer Center, Boston, MA, 2Dana-Farber Cancer Institute, Boston, MA, 3 Cleveland Clinic, Cleveland, OH, 4Broad Institute, Cambridge, MA, 5 Brigham and Women’s Hospital, Boston, MA, 6Dana-Farber Cancer Institute, Brigham and Women’s Cancer Center, Boston, MA, 7 Massachusetts Institute of Technology, Cambridge, MA Purpose/Objective(s): It is not known whether GBM patients respond differently to radiation treatment based on tumor cell-intrinsic factors. Newly developed patient-derived models of GBM have potential to help study differences in individual patient functional response to treatment at a scale not previously possible. We therefore assessed whether intrinsic differences in radiation sensitivity are present in a large panel of clinically and genomically annotated GBM PDCLs. Materials/Methods: Patient-derived cell lines were established from newly diagnosed (nZ25) and recurrent (nZ10) glioblastoma patients. Whole exome sequencing and whole genome array comparative genomic hybridization (aCGH) was performed on the PDCLs to characterize the molecular characteristics, and patient outcomes data was collected. Highthroughput functional radiation screening was performed across all patients at varying doses. Response was calculated at 9 days after treatment based on ATP measurement using Cell Titer Glow as an assessment of growth and recovery of growth after exposure to a range of doses of radiation by plotting relative luminescence units as a function of time. Proliferation was integrated as a function of dose and generated values for each cell line (AUC). AUC was correlated with genomic candidate factors and clinical outcomes. Results: Mean AUC values were normally distributed across patient models (pZ0.67 Shapiro-Wilk). The mean AUC for p53 mutant lines was 4.3 vs. 2.9 for p53 intact lines (pZ0.03). Whereas p53 mutant tumors were generally relatively resistant, p53 wild-type tumors showed significant variability in radiation sensitivity. There was no difference in radiation sensitivity between tumors derived from treatment-naı¨ve or recurrent tumors (p Z NS). There was also no correlation of intrinsic radiosensitivity with patient outcome, though the analysis was limited by sample size and significant variability related to clinical prognostic factors. Conclusion: GBM patient-derived models suggest the existence of tumor cell-intrinsic differences in radiation sensitivity across patients that correlate with p53 mutation status. Further studies are needed to validate this in vivo and in patients and to determine whether PDCL may be useful functional indicators of clinical response. Author Disclosure: M. Huynh: None. C.L. Maire: None. M. Abazeed: None. D. Adams: None. K. Pelton: None. N. Pinnell: None. S. Ramkissoon: None. H. Korideck: None. P. Van Hummelen: None. A.