Outcomes for Metastatic Melanoma Treated With Stereotactic Radiosurgery In the Era of Targeted Systemic Therapies

Volume 96  Number 2S  Supplement 2016 Purpose/Objective(s): To develop treatment plans and compare dose distributions and dose-volume histograms (DVHs) in brain anatomic and functional compartments, for passive scatter protons versus intensity modulated radiation therapy for patients with unilateral glioblastoma Materials/Methods: A series of 19 consecutive patients treated with IMRT for glioblastoma were selected for development of proton treatment plans. The group included 9 right-sided and 10 left-sided tumors. The median prescribed treatment dose was 59.04 Gy in 30-33 fractions. Plans were matched with respect to fraction size, number, and prescribed dose. Identical CTVs were treated with equivalent target coverage using both proton and IMRT planning. The median CTV volume was 332.54 cc. The overall brain volume and individual neuroanatomic compartments/structures were defined including grey matter, white matter, cerebrum, cerebellum, brainstem, hippocampus, hypothalamus, optic nerves, and optic chiasm. Treatment planning was performed and comparison DVHs were tabulated in a commercially available deformable registration algorithm. Results: The mean CTV V100 for proton plans was 98.72% and for IMRT plans was 98.67%. For both right and left-sided glioblastomas, proton planning resulted in lower mean V5 (41.79% vs 99.21%), V10 (36.19% vs 84.91%), V12 (34.27% vs 80.94%) and V20 (27.94% vs 62.02%) for uninvolved brain in comparison to IMRT planning. There was no significant difference in V5, V10, or maximum dose for ipsilateral hippocampi between protons and IMRT. For contralateral hippocampi, substantial sparing was observed using proton planning with mean V5 (Left-sided tumor: 29.21% vs 97.08%; Right-sided tumor: 24.82% vs 100%), and mean V10 (Left-sided tumor: 19.27% vs 88.71%; Right-sided tumor: 14.79% vs 99.56%) reduced relative to IMRT planning. The hypothalamic V40 was 77% for IMRT planning and 67% for protons. Optic chiasm 2mm PRV V54 was 0.42cc for IMRT planning, 0.15cc for protons. Conclusion: Radiation treatment of brain tumors may result in detrimental effects on neurocognitive function, microvasculature, behavior, and endocrine function. Glioblastoma patients typically have large treatment volumes and are susceptible to these treatment-related effects. These effects are more likely with improved survival time, and may be mitigated through dose reduction to uninvolved brain. Our comparative dosimetric results reveal that contralateral hippocampus dose as well as overall uninvolved brain dose may be substantially reduced using proton planning in patients with unilateral glioblastoma. The overall potential clinical benefit of these dosimetric advantages in glioblastoma patients remains to be determined. Author Disclosure: N.R. Ramakrishna: None. B. Harper: None. R. Burkavage: None. T. Willoughby: None. N. Avgeropoulos: None. O.A. Zeidan: None.

2329 Low Levels of Acute Toxicity Associated With Proton Therapy for Low-Grade Glioma: A Proton Collaborative Group Study B. Wilkinson,1 H. Morgan,2 V. Gondi,3 G.L. Larson,4 W.F. Hartsell,3 G.E. Laramore,5 L.M. Halasz,5 C. Vargas,6 S.R. Keole,6 D.R. Grosshans,7 H.A. Shih,8 and M.P. Mehta9; 1Willis-Knighton Cancer Center, Shreveport, LA, 2LSU Health Science Center Shreveport, Shreveport, LA, 3 Northwestern Medicine Chicago Proton Center, Warrenville, IL, 4ProCure Proton Therapy Center, Oklahoma City, OK, 5University of Washington, Department of Radiation Oncology, Seattle, WA, 6Mayo Clinic Arizona, Phoenix, AZ, 7Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 8Massachusetts General Hospital, Boston, MA, 9Miami Cancer Institute, Baptist Health South Florida, Miami, FL Purpose/Objective(s): Patients receiving proton beam therapy (PBT) for low-grade gliomas (LGG) at Proton Collaborative Group (PCG) institutions were analyzed to determine acute and chronic adverse effects. Materials/Methods: A central, IRB-approved prospective database for six proton therapy centers was queried to identify patients >21 years old who

Poster Viewing E135 were treated with PBT for LGG between 1/2010 and 12/2015. Demographic, pathologic, and treatment information were collected and analyzed. Toxicities were scored according to the CTCAE version 4.0. Toxicities both during and after treatment were evaluated and compared for correlation with PBT dose. Side effects at the end of PBT were then scored against reported toxicity at follow up. Descriptive statistics were calculated for all patients with paired-samples t-tests generated to compare toxicity grade between treatments and follow up. Results: Fifty-eight patients with a median age of 44 (range: 21 to 72) were identified. All had biopsy-proven WHO grade II glioma. Histology distribution was 33% oligodendroglioma (n Z 19), 38% astrocytoma (n Z 22), and 29% mixed oligoastrocytoma (n Z 17). Tumors predominantly involved the frontal lobe (67%), with the remainder overlapping with or individually involving the temporal (32%), parietal (12%), and occipital (2%) lobes while 1 case was multi-focal. Degree of resection was reported in 84% of cases with most receiving a sub-total resection (62%) and 33% receiving gross-total resection, with only 5% biopsy only. Fifteen patients (26%) received chemotherapy prior to PBT. Most of these patients had a pure oligodendroglioma or mixed histology tumor. Nearly all patients were treated definitively (98%), with most patients receiving between 50.4 cGyE and 54 cGyE (78%). All side effects while under treatment were either grade 1 or 2, with the most common toxicities being alopecia (81%), dermatitis (78%), fatigue (47%), and headache (40%). There were no grade 3 toxicities. The most common grade 2 acute toxicity was dermatitis (19%). In general, side effects improved over time with statistically significant reductions in grade 1-2 temporary alopecia (81% vs 40%, P<0.001), dermatitis (78% vs 39%, P<0.001), and fatigue (46% vs 23%, P<0.001) between the conclusion of PBT versus 1-3 months after therapy, respectively. No correlation between total PBT dose and toxicity grade was identified. Conclusion: Most side effects of partial brain irradiation using proton beam therapy for LGG are mild with no observed grade 3 or higher toxicities in a multi-institutional prospective patient cohort. The expected adverse that did occur improved over time in most patients. Long-term follow-up and comparison to historical rates of toxicity are indicated until randomized comparisons between IMRT and PBT are available. Author Disclosure: B. Wilkinson: None. H. Morgan: None. V. Gondi: None. G.L. Larson: None. W.F. Hartsell: Employee; Cadence Health. Partnership; CPTI, Elk Grove Radiosurgery, Illinois CyberKnife. Board Member; National Association for Proton Therapy. President; Proton Collaborative Group. G.E. Laramore: None. L.M. Halasz: None. C. Vargas: None. S.R. Keole: Board Member; ASTRO. D.R. Grosshans: None. H.A. Shih: None. M.P. Mehta: Consultant; Cavion, Novocure. Stock; Pharmacyclics. Board Member; Pharmacyclics.

2330 Outcomes for Metastatic Melanoma Treated With Stereotactic Radiosurgery In the Era of Targeted Systemic Therapies A. Henson, E. McTyre, D.N. Ayala-Peacock, P. Triozzi, P. Savage, A.W. Laxton, and M.D. Chan; Wake Forest Baptist Medical Center, Winston-Salem, NC Purpose/Objective(s): Melanoma treatment paradigms and prognoses have dramatically changed with development of targeted agents and immunotherapies that have improved overall survival and control of extracranial disease. It remains unclear, however, how the use of novel agents and BRAF status affect treatment outcomes and patterns of failure in brain metastasis patients, particularly after stereotactic radiosurgery. Materials/Methods: We performed a retrospective review of a prospectively maintained clinical database of patients at a single-institution academic medical center to identify metastatic melanoma patients treated between 2000 and 2015 with stereotactic radiosurgery (SRS). All patients had at least one post-SRS imaging study after. Patients were stratified by BRAF status into mutated, wild type, or unknown. Targeted agents were defined as BRAF inhibitors, MEK inhibitors, CTLA-4 inhibitors or PD-1 inhibitors. Time to event endpoints were summarized

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using the Kaplan-Meier estimator and Cox proportional hazard analyses were performed for overall survival, local and distant failure, and time to whole brain radiation therapy (WBRT) for patients who did not receive prior WBRT. Results: Information from 123 patients with metastatic melanoma treated with gamma knife SRS was included for analysis. BRAF status was known for 45 of the 123 patients assessed (37%). The median age was 63 (range 22- 91), 73% were male, 56% (n Z 69) of patients had a single session of SRS, and the median number of treated metastatic lesions during the first SRS session was 2 (range 1-10). The number of SRS sessions ranged from one to five, and a total of 550 lesions were treated with SRS and had available interval imaging follow-up. The use of ipilimumab was associated with improved OS (HR Z 0.51, P Z 0.006), while unknown BRAF status was associated with worsened OS (HR Z 2.57, P Z 0.002). BRAF mutation was associated with decreased local brain failure (HR Z 0.11, P Z 0.03). Number of brain metastases at first SRS was predictive of distant brain failure (HR Z 1.2, P Z 0.001), while minimum dose delivered to the metastasis was predictive of local brain failure (HR Z 0.82, P Z 0.03). Conclusion: Presence of BRAF mutation was associated with improved local control and the use of ipilimumab was associated with improved OS. Improvements in survival seen in patients with known BRAF status is most likely due to better ability to offer these patients appropriate systemic therapies. Author Disclosure: A. Henson: None. E. McTyre: None. D.N. AyalaPeacock: None. P. Triozzi: None. P. Savage: None. A.W. Laxton: None. M.D. Chan: None.

gliomas (P<0.0001). Better OS from the end of re-irradiation was seen with KPS80 (median 9.8 vs 3.7 months, P<0.0001), initial lower grade disease (14.2 vs 10.9 vs 5.1 months for grades II, III, and IV, respectively, P Z 0.001), recurrent grade III disease (12.9 vs 6.3 months for grade IV, P Z 0.007), and concurrent treatment with TMZ alone (10.7 months vs 6.6 months for BEV alone, 3.8 months for TMZ + BEV, and 4.5 months for no chemotherapy, P Z 0.02). Radiation necrosis and grade 3 late CNS toxicity were both minimal (<3%) in this group. Conclusion: Re-irradiation even at doses >36 Gy were safe, well tolerated, and completed in the majority of patients with recurrent high-grade glioma. Concurrent systemic therapy did not appear to result in increased toxicity or inability to complete therapy and was associated with longer survival, though prospective study controlling for covariates is necessary to confirm this survival advantage. Author Disclosure: C. Shen: None. K.J. Redmond: Research Grant; Elekta AB. J. Martinez-Gutierrez: None. M. Kummerlowe: None. S. Usama: None. R.E. Strowd: None. L.R. Kleinberg: None.

2331 Reirradiation for Recurrent High-Grade Glioma: Evaluation of Dose Escalation and Concurrent Chemotherapy C. Shen,1 K.J. Redmond,1 J.C. Martinez-Gutierrez,1 M. Kummerlowe,1 S.M. Usama,2 R.E. Strowd,3 and L.R. Kleinberg1; 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Dow University of Health Sciences, Karachi, Pakistan, 3Wake Forest Baptist Medical Center, Winston-Salem, NC Purpose/Objective(s): Re-irradiation for recurrent glioma remains controversial, although several studies have now suggested a dose of 36 Gy as standard in the re-treatment setting. We evaluated outcomes and toxicity following re-irradiation for recurrent high grade gliomas, in many cases to higher than 36 Gy, as well as the impact of concurrent chemotherapy. Materials/Methods: We conducted a retrospective review of 86 patients (49 men and 37 women, median age 46 [range 30-78], median KPS 80 [range 40-100]) treated with re-irradiation for recurrent high-grade glioma from 2007-2015. Patients with initial low-grade glioma that recurred as high-grade glioma were included. Outcome metrics included overall survival, prognostic factors for survival, and treatment-related toxicity. Results: At initial diagnosis, 23% of patients had WHO grade I-II glioma, 23% grade III, and 54% grade IV. At recurrence, 27% had grade III disease, and 73% grade IV. Re-irradiation occurred at a median of 29.4 months following initial radiation (range 4.8-203.3 months). The median re-irradiation dose was 41.4 Gy (range 12.6-54 Gy) to a median lesion volume of 188 cm3 (range 20-901 cm3). Of evaluable treatment plans, the median cumulative (initial- and re-irradiation combined) maximum dose to the brain stem was 77.9 Gy (range 6.2-103.4 Gy) and to the optic apparatus 54.9 Gy (range 7.2-81.7 Gy). Most re-treatments either directly overlapped the prior treatment field (43%) or overlapped but also included an adjacent region previously not treated to full dose (38%). Concurrent temozolomide (TMZ) alone was given with 52% of re-irradiation treatments, bevacizumab (BEV) alone with 14%, TMZ + BEV with 13%, and no chemotherapy with 21%. The planned course of re-irradiation was completed by 90% of patients and was not affected by concurrent chemotherapy treatment. Median overall survival (OS) from primary diagnosis was 150 months for patients with initial grade I-II gliomas, 73 months for initial grade III gliomas, and 31 months for initial grade IV

2332 Treatment Selection and Outcomes of Elderly Patients With Glioblastoma: Analysis of the National Cancer Data Base R.M. Rhome1 and R.R. Parikh2; 1Icahn School of Medicine at Mount Sinai New York, NY, 2Rutgers Cancer Institute of New Jersey, New Brunswick, NJ Purpose/Objective(s): Temozolomide given concurrently with radiation after resection/biopsy improves survival in glioblastoma (GBM). The benefit of single-agent chemotherapy and its association with outcome have not been well established in elderly (>70 years of age) patients with GBM. Materials/Methods: Using the National Cancer Database (NCDB), we evaluated clinical features and survival outcomes among elderly patients diagnosed with GBM from 1998 to 2012. The association between chemotherapy use, radiation therapy fractionation scheme, patient related co-variables, and survival outcome was assessed in a multivariate Cox proportional hazards regression model and propensity score (PS) matching was performed to balance observed confounding factors. Survival was estimated using the Kaplan-Meier method. Results: Among the 114,979 patients in the NCDB with GBM, 17,005 patients were over the age of 70 years, received post-operative radiation therapy, and met inclusion criteria for analysis. Median age was 76, and median follow-up was 6.3 months. Treatment with concurrent chemotherapy was associated with male gender, white race, relative younger age, more extensive surgery, use of standard radiation therapy fractionation scheme, higher socioeconomic quartiles, and treatment at academic/ research centers (all P<0.05). One-year overall survival for patients receiving chemotherapy was 13.0% versus 2.2% for those without chemotherapy (P<0.01). After PS-matching based on clinicopathologic characteristics, chemotherapy use remained associated with improved overall survival (HR 0.52, 95% CI, 0.44e0.61, P<0.01) for cohorts receiving either standard or hypofractionated radiation therapy schemes. Over the study time period, chemotherapy utilization increased from 9.7% to 84.2%, particularly during 2003-2004. Conclusion: Concurrent chemotherapy was associated with an improvement in overall survival for elderly (>70 years) patients with GBM, irrespective of radiation therapy dose/fractionation chosen. We have identified patient-specific variations in the use of chemotherapy that may be targeted to improve patient access to care. Author Disclosure: R.M. Rhome: None. R.R. Parikh: None.

2333 Results of Stereotactic Ablative Radiation Therapy for Pulmonary Oligometastases From Colorectal Cancer in Japan: A MultiInstitutional Survey Study of the Japanese Radiation Oncology Study Group (JROSG) K. Jingu,1 Y. Matsuo,2 H. Onishi,3 T. Yamamoto,1 M. Aoki,4 Y. Murakami,5 H. Yamashita,6 H. Kakuhara,7 K. Nemoto,8 T. Sakayauchi,9