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We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.Patients (23% of patients developed myelotoxicity (Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

Purpose Stereotactic radiosurgery (SRS) is increasingly used in the management of patients with resected brain metastases (rBMs). A significant complication of this therapy can be radiation necrosis (RN). Despite radiation therapy dose de-escalation and the delivery of several rather than a single dose fraction, rates of RN after SRS for rBMs remain high. We evaluated the dosimetric parameters associated with radiographic RN for rBMs. Methods and Materials From 2008 to 2016, 55 rBMs at a single institution that were treated postoperatively with 5-fraction linear accelerator–based SRS (25-35 Gy) with minimum 3 months follow-up were evaluated. For each lesion, variables recorded included radiation therapy dose to normal brain, location and magnitude of hotspots, clinical target volume (CTV), and margin size. Hotspot location was stratified as within the tumor bed alone (CTV) or within the planning target volume (PTV) expansion margin volume (PTV minus CTV). Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence. Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. Results Median age for all patients was 58.5 years. For all targets, the median CTV was 17.53 cm3, the median expansion margin to PTV was 2 mm, and the median max hotspot was 111%. At 1 year, cumulative incidence of radiographic RN was 18.2%. Univariate analysis showed that max hotspots with a hazard ratio of 3.28 (P = .045), hotspots within the PTV expansion margin with relative magnitudes of 105%, 110%, and 111%, and an absolute dose of 33.5 Gy predicted for RN (P = .029, P = .04, P = .038, and P = .0488, respectively), but hotspots within the CTV did not. Conclusions To our knowledge, this is the first study that investigated dosimetric factors that predict for RN after 5-fraction hypofractionated SRS for rBM. Hotspot location and magnitude appear important for predicting RN risk, thus these parameters should be carefully considered during treatment planning.

Background We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02–3.27) and being female (OR, 4.45; 95% CI, 2.45–8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43–1.89). Conclusions Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

OBJECTIVEThe optimal margin size in postoperative stereotactic radiosurgery (SRS) for brain metastases is unknown. Herein, the authors investigated the effect of SRS planning target volume (PTV) margin on local recurrence and symptomatic radiation necrosis postoperatively.METHODSRecords of patients who received postoperative LINAC-based SRS for brain metastases between 2006 and 2016 were reviewed and stratified based on PTV margin size (1.0 or > 1.0 mm). Patients were treated using frameless and framed SRS techniques, and both single-fraction and hypofractionated dosing were used based on lesion size. Kaplan-Meier and cumulative incidence models were used to estimate survival and intracranial outcomes, respectively. Multivariate analyses were also performed.RESULTSA total of 133 patients with 139 cavities were identified; 36 patients (27.1%) and 35 lesions (25.2%) were in the 1.0-mm group, and 97 patients (72.9%) and 104 lesions (74.8%) were in the > 1.0–mm group. Patient characteristics were balanced, except the 1.0-mm cohort had a better Eastern Cooperative Group Performance Status (grade 0: 36.1% vs 19.6%), higher mean number of brain metastases (1.75 vs 1.31), lower prescription isodose line (80% vs 95%), and lower median single fraction–equivalent dose (15.0 vs 17.5 Gy) (all p < 0.05). The median survival and follow-up for all patients were 15.6 months and 17.7 months, respectively. No significant difference in local recurrence was noted between the cohorts. An increased 1-year rate of symptomatic radionecrosis was seen in the larger margin group (20.9% vs 6.0%, p = 0.028). On multivariate analyses, margin size > 1.0 mm was associated with an increased risk for symptomatic radionecrosis (HR 3.07, 95% CI 1.13–8.34; p = 0.028), while multifraction SRS emerged as a protective factor for symptomatic radionecrosis (HR 0.13, 95% CI 0.02–0.76; p = 0.023).CONCLUSIONSExpanding the PTV margin beyond 1.0 mm is not associated with improved local recurrence but appears to increase the risk of symptomatic radionecrosis after postoperative SRS.

Background Results of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints. Methods NCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated. Results A total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference. Conclusion The collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.

PURPOSE NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Allele-specific copy number analysis of tumors (ASCAT) assesses copy number variations (CNV) while accounting for aberrant cell fraction and tumor ploidy. We evaluated if ASCAT-assessed CNV are associated with survival outcomes in 56 patients with WHO grade IV gliomas. Tumor data analyzed by Affymetrix OncoScan FFPE Assay yielded the log ratio (R) and B-allele frequency (BAF). Input into ASCAT quantified CNV using the segmentation function to measure copy number inflection points throughout the genome. Quantified CNV was reported as log R and BAF segment counts. Results were confirmed on The Cancer Genome Atlas (TCGA) glioblastoma dataset. 25 (44.6%) patients had MGMT hyper-methylated tumors, 6 (10.7%) were IDH1 mutated. Median follow-up was 36.4 months. Higher log R segment counts were associate with longer progression-free survival (PFS) [hazard ratio (HR) 0.32, p < 0.001], and overall survival (OS) [HR 0.45, p = 0.01], and was an independent predictor of PFS and OS on multivariable analysis. Higher BAF segment counts were linked to longer PFS (HR 0.49, p = 0.022) and OS (HR 0.49, p = 0.052). In the TCGA confirmation cohort, longer 12-month OS was seen in patients with higher BAF segment counts (62.3% vs. 51.9%, p = 0.0129) and higher log R (63.6% vs. 55.2%, p = 0.0696). Genomic CNV may be a novel prognostic biomarker for WHO grade IV glioma patient outcomes.

PURPOSE: For treatment of choroidal melanoma, Palladium-103 ((103)Pd) and Ruthenium-106 ((106)Ru) plaque brachytherapy demonstrates reduced toxicity compared to the historical standard Iodine-125 ((125)I). No report has directly compared clinical outcomes between (103)Pd and (106)Ru, and reasons for selection of one over the other remain purely theoretical. MATERIALS/METHODS: Patients with choroidal melanoma with apical tumor height ≤ 5 mm were included. Patients from Emory University were treated with (103)Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with (106)Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. RESULTS: (103)Pd patients (n = 124) and (106)Ru patients (n = 42) had median follow up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes but (106)Ru had lower grades of retinopathy (p=0.006). (103)Pd was associated with worse VA preservation (≥20/40) by year 3 (OR 3.8, 95% CI 1.01–14.31, p=0.048). (103)Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (MVA) (HR 0.10, 95% CI 0.02–0.38, p

BACKGROUND The addition of chemotherapy to adjuvant radiotherapy (chemotherapy and radiation therapy [CRT]) improves overall survival (OS) for patients with high-risk grade 2 gliomas; however, the impact of chemotherapy alone (CA) is unknown. This study compares the OS of patients with high-risk grade 2 gliomas treated with CA versus CRT. METHODS Patients with high-risk grade 2 gliomas (subtotal resection or age ≥ 40 years) with oligodendrogliomas, astrocytomas, or mixed tumors were identified with the National Cancer Data Base. Patients were grouped into CA and CRT cohorts. Univariate analyses and multivariate analyses (MVAs) were performed. Propensity score (PS) matching was also implemented. The Kaplan-Meier method was used to analyze OS. RESULTS A total of 1054 patients with high-risk grade 2 gliomas were identified: 496 (47.1%) received CA, and 558 (52.9%) received CRT. Patients treated with CA were more likely (all P values 6 cm, astrocytoma histology, and older age were predictors for worse OS (all P values

Although historical trials have established the role of surgical resection followed by whole brain irradiation (WBRT) for brain metastases, WBRT has recently been shown to cause significant neurocognitive decline. Many practitioners have employed postoperative stereotactic radiosurgery (SRS) to tumor resection cavities to increase local control without causing significant neurocognitive sequelae. However, studies analyzing outcomes of large brain metastases treated with resection and postoperative SRS are lacking. Here we compare outcomes in patients with large brain metastases4 cm to those with smaller metastases ≤4 cm treated with surgical resection followed by SRS to the resection cavity.Consecutive patients with brain metastases treated at our institution with surgical resection and postoperative SRS were retrospectively reviewed. Patients were stratified into ≤4 cm and4 cm cohorts based on preoperative maximal tumor dimension. Cumulative incidence of local failure, radiation necrosis, and death were analyzed for the 2 cohorts using a competing-risk model, defined as the time from SRS treatment date to the measured event, death, or last follow-up.A total of 117 consecutive cases were identified. Of these patients, 90 (77%) had preoperative tumors ≤4 cm, and 27 (23%)4 cm in greatest dimension. The only significant baseline difference between the 2 groups was a higher proportion of patients who underwent gross total resection in the ≤4 cm compared with the4 cm cohort, 76% versus 48%, respectively (P.01). The 1-year rates of local failure, radiation necrosis, and overall survival for the ≤4 cm and4 cm cohorts were 12.3% and 16.0%, 26.9% and 28.4%, and 80.6% and 67.6%, respectively (all P.05). The rates of local failure and radiation necrosis were not statistically different on multivariable analysis based on tumor size.Brain metastases4 cm in largest dimension managed by resection and radiosurgery to the tumor cavity have promising local control rates without a significant increase in radiation necrosis on our retrospective review.

Purpose Stereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs. Methods and Materials A large BM was defined as ≥4 cm3 (2 cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single-fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions. Results Overall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9 cm3 vs 9.6 cm3; P Conclusions In this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted.

Purpose To evaluate outcomes of choroidal melanoma patients treated with 125I or 103Pd plaque brachytherapy. Methods and Materials From 1993 to 2012, our institution treated 160 patients with 103Pd (56.1%) and 125 patients with 125I (43.9%) plaque brachytherapy. Tumor outcomes, visual acuity (VA), and toxicity were compared. Multivariate analyses (MVAs) and propensity score analysis were used to help address differences in baseline characteristics. Results Median followup was longer for 125I patients, 52.7 vs. 43.5 months (p 90% 3-year overall survival and >93% 5-year secondary enucleation-free survival. On MVA, radionuclide was not predictive for tumor outcomes. A higher percentage maintained vision better than 20/40 with 103Pd (63% vs. 35%, p = 0.007) at 3 years. MVA demonstrated 103Pd radionuclide (odds ratio [OR]: 2.12, p = 0.028) and tumor height ≤5 mm (OR: 2.78, p = 0.017) were associated with VA better than 20/40. Propensity score analysis matched 23 125I with 107 103Pd patients. 103Pd continued to predict better VA at 3 years (OR: 8.10, p = 0.014). On MVA for the development of VA worse than 20/200 or degree of vision loss, radionuclide was not significant. Lower rates of radiation retinopathy were seen with 103Pd than 125I (3 years: 47.3% vs. 63.9%, p = 0.016), with radionuclide significant in MVA. Conclusions Both 125I and 103Pd achieve excellent tumor control. An increased probability of long-term VA better than 20/40 and reduced risk of radiation retinopathy is associated with 103Pd.

Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan-Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, p = 0.001) and smaller median lesion volume (8.3 cc vs. 15.3 cc, p = 0.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (p = 0.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (p = 0.81), distant brain failure (DBF): 53.2% vs. 45% (p = 0.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (p = 0.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post-WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed.

BACKGROUND Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

Background: To investigate the impact of proton radiotherapy (PBT) on overall survival (OS) and evaluate PBT usage trends for patients with gliomas in the National Cancer Data Base (NCDB). Methods: Patients with a diagnosis of World Health Organization (WHO) Grade I-IV glioma treated with definitive radiation therapy (RT) between the years of 2004–13 were identified. Patients were stratified based on WHO Grade and photon radiotherapy (XRT) vs. PBT. Univariate (UVA) and multivariable analysis (MVA) with OS were performed by Cox proportional hazards model and log-rank tests. Propensity score (PS) weighting was utilized to account for differences in patient characteristics and to minimize selection bias. Results: There were a total of 49,405 patients treated with XRT and 170 patients treated with PBT. Median follow-up time was 62.1 months. On MVA, the following factors were associated with receipt of PBT (all p < 0.05): WHO Grade I-II gliomas, treatment at an academic/research program, west geographic facility location, and surgical resection. After PS weighting, all patients treated with PBT were found to have superior median and 5 year survival than patients treated with XRT: 45.9 vs. 29.7 months (p = 0.009) and 46.1 vs. 35.5% (p = 0.0160), respectively. Conclusions: PBT is associated with improved OS compared to XRT for patients with gliomas. This finding warrants verification in the randomized trial setting in order to account for potential patient imbalances not adequately captured by the NCDB, such as tumor molecular characteristics and patient performance status. Importance of the Study: This is the first study that compares the outcomes of patients treated with photon based radiotherapy vs. proton based radiotherapy for patients with gliomas. In this retrospective analysis, the results demonstrate that proton therapy is associated with improved outcomes which support ongoing prospective, randomized clinical trials comparing the two modalities in patients with gliomas.

Objective Both stereotactic radiosurgery (SRS) and fractionated radiation therapy (FRT) techniques are used for treatment of intracranial meningiomas with excellent local control (LC) rates. Although SRS techniques are convenient, toxicity including treatment-related edema can significantly impact patient quality of life. The long-term clinical outcomes of patients with magnetic resonance imaging (MRI)–defined meningiomas treated with radiation therapy (RT) alone are reported. Methods The charts of 211 patients with meningiomas diagnosed by contrast-enhanced MRI treated with either SRS or FRT between 1991 and 2012 at a single institution were reviewed. Actuarial rates for LC and development of treatment-related radiographic edema (TRE) were determined by the Kaplan-Meier method. Results There were 211 patients who received radiation therapy for 223 lesions. Median follow-up was 5.7 years. Eleven patients experienced a local failure; of these, 2 were ultimately found to have pathologically proven metastatic carcinoma. Two- and 5-year LC was 97.8% and 94.6%, respectively, with no significant difference based on modality of therapy. Actuarial rate for development of TRE at 1 and 2 years was 30.1% and 34.6% for the SRS group and 1.6% and 2.5% for the FRT group, respectively (P Conclusions RT alone using a limited margin is an effective treatment option for MRI-defined meningiomas and should be considered even without biopsy if surgery will present significant morbidity. Although LC with SRS versus FRT was comparable, FRT was associated with a significantly decreased risk of TRE.

Background Brain metastases (BM) treated with surgical resection and focal postoperative radiotherapy have been associated with an increased risk of subsequent leptomeningeal dissemination (LMD). BMs with hemorrhagic and/or cystic features contain less solid components and may therefore be at higher risk for tumor spillage during resection. Objective To investigate the association between hemorrhagic and cystic BMs treated with surgical resection and stereotactic radiosurgery and the risk of LMD. Methods One hundred thirty-four consecutive patients with a single resected BM treated with adjuvant stereotactic radiosurgery from 2008 to 2016 were identified. Intracranial outcomes including LMD were calculated using the cumulative incidence model with death as a competing risk. Univariable analysis and multivariable analysis were assessed using the Fine & Gray model. Overall survival was analyzed using the Kaplan-Meier method. Results Median imaging follow-up was 14.2 mo (range 2.5-132 mo). Hemorrhagic and cystic features were present in 46 (34%) and 32 (24%) patients, respectively. The overall 12- and 24-mo cumulative incidence of LMD with death as a competing risk was 11.0 and 22.4%, respectively. On multivariable analysis, hemorrhagic features (hazard ratio [HR] 2.34, P = .015), cystic features (HR 2.34, P = .013), breast histology (HR 3.23, P = .016), and number of brain metastases >1 (HR 2.09, P = .032) were independently associated with increased risk of LMD. Conclusion Hemorrhagic and cystic features were independently associated with increased risk for postoperative LMD. Patients with BMs containing these intralesion features may benefit from alternative treatment strategies to mitigate this risk.

Treatment planning for whole‐brain radiation treatment is technically a simple process, but in practice it takes valuable clinical time of repetitive and tedious tasks. This report presents a method that automatically segments the relevant target and normal tissues, and creates a treatment plan in only a few minutes after patient simulation. Segmentation of target and critical structures is performed automatically through morphological operations on the soft tissue and was validated by comparing with manual clinical segmentation using the Dice coefficient and Hausdorff distance. The treatment plan is generated by searching a database of previous cases for patients with similar anatomy. In this search, each database case is ranked in terms of similarity using a customized metric designed for sensitivity by including only geometrical changes that affect the dose distribution. The database case with the best match is automatically modified to replace relevant patient info and isocenter position while maintaining original beam and MLC settings. Fifteen patients with marginally acceptable treatment plans were used to validate the method. In each of these cases the anatomy was accurately segmented, but the beams and MLC settings led to a suboptimal treatment plan by either underdosing the brain or excessively irradiating critical normal tissues. For each case, the anatomy was automatically segmented with the proposed method, and the automated and manual segmentations were then compared. The mean Dice coefficient was 0.97, with a standard deviation of 0.008 for the brain, 0.85±0.009 for the eyes, and 0.67±0.11 for the lens. The mean Euclidian distance was 0.13±0.13 mm for the brain, 0.27±0.31 for the eye, and 2.34±7.23 for the lens. Each case was then subsequently matched against a database of 70 validated treatment plans and the best matching plan (termed autoplanned), was compared retrospectively with the clinical plans in terms of brain coverage and maximum doses to critical structures. Maximum doses were reduced by a maximum of 8.37 Gy for the left eye (mean 2.08), 11.67 for the right eye (1.90) and, respectively, 25.44 (5.59) for the left lens and 24.40 (4.85) for the right lens. Time to generate the autoplan, including the segmentation, was 3−4 min. Automated database‐ based matching is an alternative to classical treatment planning that improves quality while providing a cost‐effective solution to planning through modifying previous validated plans to match a current patient's anatomy. PACS number: 87.55.D, 87.55.tg, 87.57.nm

BACKGROUND The purpose of this study was to evaluate predictors of early distant brain failure (DBF) and salvage whole-brain radiotherapy (WBRT) after treatment with stereotactic radiosurgery (SRS) for brain metastases and create a clinically relevant risk score to stratify patients’ risk for these events. METHODS The records of 270 patients with brain metastases who were treated with SRS between 2003 and 2012 were reviewed. Pretreatment patient and tumor characteristics were analyzed with univariate and multivariate analyses. The cumulative incidences of first DBF and salvage WBRT were calculated. Significant factors were used to create a score for stratifying early (6-month) DBF risk. RESULTS No prior WBRT, a total lesion volume

The purpose of this study is to compare the safety and efficacy of single fraction radiosurgery (SFR) with hypofractionated radiosurgery (HR) for the adjuvant treatment of large, surgically resected brain metastases. Seventy-five patients with 76 resection cavities ≥ 3 cm received 15 Gray (Gy) × 1 SFR (n = 40) or 5–8 Gy × 3–5 HR (n = 36). Cumulative incidence of local failure (LF) and radiation necrosis (RN) was estimated accounting for death as a competing risk and compared with Gray’s test. The effect of multiple covariates was evaluated with the Fine-Gray proportional hazards model. The most common HR dose-fractionation schedules were 6 Gy × 5 (44 %), 7–8 Gy × 3 (36 %), and 6 Gy × 4 (8 %). The median follow-up was 11 months (range 2–71). HR patients had larger median resection cavity volumes (24.0 vs. 13.3 cc, p < 0.001), planning target volumes (PTV) (37.7 vs. 20.5 cc, p < 0.001), and cavity to PTV expansion margins (2 vs. 1.5 mm, p = 0.002) than SFR patients. Cumulative incidence of LF (95 % CI) at 6 and 12-months for HR versus SFR was 18.9 % (0.07–0.34) versus 15.9 % (0.06–0.29), and 25.6 % (0.12–0.42) versus 27.2 % (0.14–0.42), p = 0.80. Cumulative incidence of RN (95 % CI) at 6 and 12 months for HR vs. SFR was 3.3 % (0.00–0.15) versus 10.7 % (0.03–0.23), and 10.3 % (0.02–0.25) versus 19.2 % (0.08–0.34), p = 0.28. On multivariable analysis, SFR was significantly associated with an increased risk of RN, with a HR of 3.81 (95 % CI 1.04–13.93, p = 0.043). Hypofractionated radiosurgery may be the more favorable treatment approach for radiosurgery of cavities 3–4 cm in size and greater.

BACKGROUND Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor and is approved for the treatment of patients with recurrent glioblastoma (GBM). Previous authors have reported differential response to bevacizumab on an individual basis. Bevacizumab-induced hypertension is a well-documented side effect, and some reports have suggested this occurrence to be related to treatment outcome in other cancers. In the current study, the authors analyzed patients with recurrent GBM who were treated with bevacizumab based on whether the patients developed drug-induced hypertension. METHODS All patients with GBM treated within the Emory Healthcare system from 2007 through 2012 were reviewed. A total of 82 patients were identified who received bevacizumab for the treatment of recurrent GBM and were included in the current study. Patients were classified as normotensive or hypertensive depending on whether hypertension developed that was attributable to therapy. Progression-free survival (PFS) and overall survival (OS) were graphed by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards method. RESULTS The median follow-up was 19.7 months. Of the 82 patients with recurrent GBM who were treated with bevacizumab, 30 developed drug-induced hypertension. The median time to the development of hypertension was 21 days. The median PFS for the normotensive and hypertensive groups were 2.5 months (95% confidence interval [95% CI], 1.6-3.0 months) and 6.7 months (95% CI, 4.6-10.0 months), respectively (P

The addition of chemotherapy to adjuvant radiotherapy (chemotherapy and radiation therapy [CRT]) improves overall survival (OS) for patients with high-risk grade 2 gliomas; however, the impact of chemotherapy alone (CA) is unknown. This study compares the OS of patients with high-risk grade 2 gliomas treated with CA versus CRT.Patients with high-risk grade 2 gliomas (subtotal resection or age ≥ 40 years) with oligodendrogliomas, astrocytomas, or mixed tumors were identified with the National Cancer Data Base. Patients were grouped into CA and CRT cohorts. Univariate analyses and multivariate analyses (MVAs) were performed. Propensity score (PS) matching was also implemented. The Kaplan-Meier method was used to analyze OS.A total of 1054 patients with high-risk grade 2 gliomas were identified: 496 (47.1%) received CA, and 558 (52.9%) received CRT. Patients treated with CA were more likely (all P values .05) to have oligodendroglioma histology (65.5% vs 34.2%), exhibit a 1p/19q codeletion (22.8% vs 7.5%), be younger (median age, 47.0 vs 48.0 years), and receive treatment at an academic facility (65.2% vs 50.3%). The treatment type was not a significant predictor for OS (P = .125) according to the MVA; a tumor size 6 cm, astrocytoma histology, and older age were predictors for worse OS (all P values .05). After 1:1 PS matching (n = 331 for each cohort), no OS difference was seen (P = .696) between the CA and CRT cohorts at 5 (69.3% vs 67.4%) and 8 years (52.8% vs 56.7%).No long-term OS difference was seen in patients with high-risk grade 2 gliomas treated with CA versus CRT. These findings are hypothesis-generating, and prospective clinical trials comparing these treatment paradigms are warranted. Cancer 2018;124:1169-78. © 2017 American Cancer Society.

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3–4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

Object Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability. Methods Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations. Results There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (κ = 0.96) when compared with 2D (κ = 0.54) or 1D (κ = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94). Conclusions Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.

The treatment of patients who experience intracranial progression after whole brain radiation therapy (WBRT) is a clinical challenge. Novel radiation therapy delivery technologies are being applied with the objective of improving tumor and symptom control in these patients. The purpose of this study is to describe the clinical outcomes of the application of a novel technology to deliver repeat WBRT with volume modulated arc therapy (VMAT) and a simultaneous infield boost (WB-SIB) to gross disease. A total of 16 patients were initially treated with WBRT between 2000 and 2008 and then experienced intracranial progression, were treated using repeat WB-SIB, and were analyzed. The median dose for the first course of WBRT was 35 Gy (range: 30–50.4 Gy). Median time between the initial course of WBRT and repeat WB-SIB was 11.3 months. The median dose at reirradiation was 20 Gy to the whole brain with a median boost dose of 30 Gy to gross disease. A total of 2 patients demonstrated radiographic disease progression after treatment. The median overall survival (OS) time from initial diagnosis of brain metastases was 18.9 months (range: 7.1–66.6 (95% CI: 0.8–36.9)). The median OS time after initiation of reirradiation for all patients was 2.7 months (range: 0.46–14.46 (95% CI: 1.3–8.7)). Only 3 patients experienced CTCAE grade 3 fatigue. No other patients experienced any ≥ CTCAE grade 3 toxicity. This analysis reports the result of a novel RT delivery technique for the treatment of patients with recurrent brain metastases. Side effects were manageable and comparable to other conventional repeat WBRT series. Repeat WB-SIB using the VMAT RT delivery technology is feasible and appears to have acceptable short-term acute toxicity. These results may provide a foundation for further exploration of the WB-SIB technique for repeat WBRT in future prospective clinical trials.

BACKGROUND The patterns of lobar involvement, optimal treatment, and disease course among patients with gliomatosis cerebri (GC) have not been fully characterized. The current study evaluates the clinical presentations and outcomes for patients with GC treated with radiation therapy (RT) at our institution. METHODS A total of 26 patients (25 with follow-up) with GC were diagnosed and treated between January 2004 and June 2012. Inclusion criteria consisted of brain magnetic resonance imaging and neuroradiology confirmation of contiguous involvement of ≥ 3 lobes/lobar equivalents with preservation of neural architecture. Patients were treated with either partial-brain RT to involved tumor (25 patients) or whole-brain RT (1 patient). The median RT dose was 54.0 Gray. The median follow-up was 17.3 months. RESULTS The median age of the patients at the time of diagnosis was 57 years. Twenty-one patients (81%) and 5 patients (19%) had 3 to 6 and ≥ 7 involved lobes/lobar equivalents, respectively. The median progression-free survival and overall survival were 7.4 months and 14.9 months, respectively. Fifteen patients experienced radiographic disease progression after partial-brain RT, 14 of whom (93%) developed infield disease recurrence. On univariate analysis, higher tumor grade and type II GC (with focal mass) were associated with a poorer progression-free survival. The extent of lobar involvement and chemotherapy were not associated with overall survival. CONCLUSIONS Even with partial-brain RT, nearly all disease recurrences were infield and clinical outcomes were similar to previous GC series, thereby suggesting that whole-brain RT is not necessary for this patient population. A greater number of involved lobes did not correlate with inferior outcomes. Further studies are necessary to establish more uniform and optimal treatments for this rare disease. Cancer 2014;120:2713–2720. © 2014 American Cancer Society.

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Due to glioblastoma's infiltrative nature, an optimal radiation therapy (RT) plan requires targeting infiltration not identified by anatomical magnetic resonance imaging (MRI). Here, high-resolution, whole-brain spectroscopic MRI (sMRI) is used to describe tumor infiltration alongside anatomical MRI and simulate the degree to which it modifies RT target planning. In 11 patients with glioblastoma, data from preRT sMRI scans were processed to give high-resolution, whole-brain metabolite maps normalized by contralateral white matter. Maps depicting choline to N-Acetylaspartate (Cho/NAA) ratios were registered to contrast-enhanced T1-weighted RT planning MRI for each patient. Volumes depicting metabolic abnormalities (1.5-, 1.75-, and 2.0-fold increases in Cho/NAA ratios) were compared with conventional target volumes and contrast-enhancing tumor at recurrence. sMRI-modified RT plans were generated to evaluate target volume coverage and organ-at-risk dose constraints. Conventional clinical target volumes and Cho/NAA abnormalities identified significantly different regions of microscopic infiltration with substantial Cho/NAA abnormalities falling outside of the conventional 60 Gy isodose line (41.1, 22.2, and 12.7 cm3, respectively). Clinical target volumes using Cho/NAA thresholds exhibited significantly higher coverage of contrast enhancement at recurrence on average (92.4%, 90.5%, and 88.6%, respectively) than conventional plans (82.5%). sMRI-based plans targeting tumor infiltration met planning objectives in all cases with no significant change in target coverage. In 2 cases, the sMRI-modified plan exhibited better coverage of contrast-enhancing tumor at recurrence than the original plan. Integration of the high-resolution, whole-brain sMRI into RT planning is feasible, resulting in RT target volumes that can effectively target tumor infiltration while adhering to conventional constraints.

2002 Background: This study sought to update the predictive significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/noncodel, and IDHmt/codel) in the subset of specimens available for analysis in NRG Oncology/RTOG 9802, a phase III trial of high-risk low-grade gliomas (LGGs) treated with radiation (RT) with and without PCV after biopsy/surgical resection. Notably, this is the first phase III study to evaluate the predictive value of the WHO subgroups in LGGs using prospectively-collected, well-annotated long-term overall survival data, in a post-hoc analysis. Methods: IDH1/2 mutation status was determined by immunohistochemistry and/or next-generation sequencing. 1p/19q status was determined by Oncoscan and/or 450K methylation data. Treatment effects on overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a secondary and exploratory analysis. Results: Of all the randomized eligible high-risk G2 patients (N = 251) in NRG Oncology/RTOG 9802, 106(42%) patients had tissue available with sufficient quality DNA for profiling. Of these, 80(75%) were IDHmut; 43(41%) were IDHmut/non-co-deleted, 37(35%) were IDHmut/co-deleted, and 26(24%) were IDHwt. Upon univariate analyses, no significant difference in either PFS or OS was observed with the addition of PCV in the IDHwt subgroup. Both the IDHmut/non-co-deleted and IDHmut/co-deleted subgroups were significantly correlated with longer PFS (HR = 0.32; p = 0.003; HR = 0.13; p < 0.001) and OS (HR = 0.38; p = 0.013; HR = 0.21; p = 0.029) in the RT plus PCV arm, respectively. Conclusions: Our analyses suggest that both IDHmut/non-co-deleted and IDHmut/co-deleted subgroups received benefit from treatment with PCV although sample size is limited and analyses are post-hoc. Our results also support the notion that IDHwt high-risk LGG patients do not benefit from the addition of PCV to RT. Funding: U10CA180868, U10CA180822, and U24CA196067. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC). Clinical trial information: NCT00003375.

Purpose To retrospectively evaluate institutional outcomes for patients treated with modern radiation therapy (RT) for biopsied orbital pseudotumor (OP). Methods and Materials Twenty patients (26 affected orbits) with OP were treated with RT between January 2002 and December 2011. All patients underwent biopsy with histopathologic exclusion of other disease processes. Sixteen patients (80%) were treated with intensity modulated RT, 3 (15%) with opposed lateral beams, and 1 (5%) with electrons. Median RT dose was 27 Gy (range 25.2-30.6 Gy). Response to RT was evaluated at 4 months post-RT. Partial response (PR) was defined as improvement in orbital symptoms without an increase in steroid dose. Complete response (CR) 1 and CR 2 were defined as complete resolution of orbital symptoms with reduction in steroid dose (CR 1) or complete tapering of steroids (CR 2). The median follow-up period was 18.6 months (range 4-81.6 months). Results Seventeen patients (85%) demonstrated response to RT, with 7 (35%), 1 (5%), and 9 (45%) achieving a PR, CR 1, and CR 2, respectively. Of the 17 patients who had ≥PR at 4 months post-RT, 6 (35%) experienced recurrence of symptoms. Age (>46 years vs ≤46 years, P =.04) and clinical response to RT (CR 2 vs CR 1/PR, P =.05) were significantly associated with pseudotumor recurrence. Long-term complications were seen in 7 patients (35%), including 4 with cataract formation, 1 with chronic dry eye, 1 with enophthalmos, and 1 with keratopathy. Conclusions RT is an effective treatment for improving symptoms and tapering steroids in patients with a biopsy supported diagnosis of OP. Older age and complete response to RT were associated with a significantly reduced probability of symptom recurrence. The observed late complications may be related to RT, chronic use of steroids/immunosuppressants, medical comorbidities, or combination of factors.

Background A scoring system using pre-treatment factors was recently published ( Press et al., Cancer 2015) for predicting risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiotherapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT, (2) melanoma or breast histology, (3) multiple brain metastases, and (4) total volume of brain metastases 3 , with each factor assigned 1 point. The purpose of this study was to assess this scoring system's validity and appropriateness for clinical use in an independent external patient population. Methods We reviewed records of 247 patients with 388 brain metastases treated with SRS between 2010-2013 at XXXX. The Press (Emory) risk score was calculated and applied to the validation cohort population and subsequent risk groups were analyzed using cumulative incidence. Results The low risk (LR) group had a significantly lower risk of early DBF compared to high risk (HR) group (22.6% vs. 44%, p=0.004), but there was no difference between the HR and intermediate risk (IR) groups (41.2% vs. 44%, p=0.79). Total lesion volume 3 (p=0.004), malignant melanoma (p=0.007), and multiple metastases (p Conclusion The 3 level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR (combined IR and HR)] for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.

Frameless radiosurgery is an attractive alternative to the framed procedure if it can be performed with comparable precision in a reasonable time frame. Here, we present a positioning approach for frameless radiosurgery based on in‐room volumetric imaging coupled with an advanced six‐degrees‐of‐freedom (6 DOF) image registration technique which avoids use of a bite block. Patient motion is restricted with a custom thermoplastic mask. Accurate positioning is achieved by registering a cone‐beam CT to the planning CT scan and applying all translational and rotational shifts using a custom couch mount. System accuracy was initially verified on an anthropomorphic phantom. Isocenters of delineated targets in the phantom were computed and aligned by our system with an average accuracy of 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively. The accuracy in the rotational directions was 0.1°, 0.2°, and 0.1° in the pitch, roll, and yaw, respectively. An additional test was performed using the phantom in which known shifts were introduced. Misalignments up to 10 mm and 3° in all directions/rotations were introduced in our phantom and recovered to an ideal alignment within 0.2 mm, 0.3 mm, and 0.4 mm in the lateral, vertical, and longitudinal directions, respectively, and within 0.3° in any rotational axis. These values are less than couch motion precision. Our first 28 patients with 38 targets treated over 63 fractions are analyzed in the patient positioning phase of the study. Mean error in the shifts predicted by the system were less than 0.5 mm in any translational direction and less than 0.3° in any rotation, as assessed by a confirmation CBCT scan. We conclude that accurate and efficient frameless radiosurgery positioning is achievable without the need for a bite block by using our 6 DOF registration method. This system is inexpensive compared to a couch‐based 6 DOF system, improves patient comfort compared to systems that utilize a bite block, and is ideal for the treatment of pediatric patients with or without general anesthesia, as well as of patients with dental issues. From this study, it is clear that only adjusting for 4 DOF may, in some cases, lead to significant compromise in PTV coverage. Since performing the additional match with 6 DOF in our registration system only adds a relatively short amount of time to the overall process, we advocate making the precise match in all cases. PACS number: 87.55.tm; 87.55.Qr; 87.57.nj

Purpose To describe the use of radiosurgery (RS) alone to the resection cavity after resection of brain metastases as an alternative to adjuvant whole-brain radiotherapy (WBRT). Methods and Materials Sixty-two patients with 64 cavities were treated with linear accelerator–based RS alone to the resection cavity after surgical removal of brain metastases between March 2007 and August 2010. Fifty-two patients (81%) had a gross total resection. Median cavity volume was 8.5 cm 3 . Forty-four patients (71%) had a single metastasis. Median marginal and maximum doses were 18 Gy and 20.4 Gy, respectively. Sixty-one cavities (95%) had gross tumor volume to planning target volume expansion of ≥1 mm. Results Six-month and 1-year actuarial local recurrence rates were 14% and 22%, respectively, with a median follow-up period of 9.7 months. Six-month and 1-year actuarial distant brain recurrence, total intracranial recurrence, and freedom from WBRT rates were 31% and 51%, 41% and 63%, and 91% and 74%, respectively. The symptomatic cavity radiation necrosis rate was 8%, with 2 patients (3%) undergoing surgery. Of the 11 local failures, 8 were in-field, 1 was marginal, and 2 were both (defined as in-field if ≥90% of recurrence within the prescription isodose and marginal if ≥90% outside of the prescription isodose). Conclusions The high rate of in-field cavity failure suggests that geographic misses with highly conformal RS are not a major contributor to local recurrence. The current dosing regimen derived from Radiation Therapy Oncology Group protocol 90-05 should be optimized in this patient population before any direct comparison with WBRT.

Spinal metastasis is a problem that afflicts many cancer patients. Traditionally, conventional fractionated radiation therapy and/or surgery have been the most common approaches for managing such patients. Through technical advances in radiotherapy, high dose radiation with extremely steep drop off can now be delivered to a limited target volume along the spine under image-guidance with very high precision. This procedure, known as stereotactic body radiosurgery, provides a technique to rapidly treat selected spinal metastasis patients with single- or limited-fraction treatments that have similar to superior efficacies compared with more established approaches. This review describes current treatment systems in use to deliver stereotactic body radiosurgery as well as results of some of the larger case series from a number of institutions that report outcomes of patients treated for spinal metastatic disease. These series include nearly 1400 patients and report a cumulative local control rate of 90% with myelopathy risk that is significantly less than 1%. Based on this comprehensive review of the literature, we believe that stereotactic body radiosurgery is an established treatment modality for patients with spinal metastatic disease that is both safe and highly effective.

PURPOSE: Stereotactic Radiosurgery (SRS) is increasingly utilized in the management of resected brain metastases (rBM). A significant complication is radiation necrosis (RN) due to larger target size. Despite dose de-escalation and hypofractionation, rates of RN after SRS to rBM remain high. The aim of this analysis is to evaluate dosimetric parameters associated with RN for rBM. METHODS: From 2008–2016, 55 rBM in 52 patients at a single institution that were treated with 5 fraction LINAC based SRS (25-35Gy) with a minimum 3 months follow-up were evaluated. For each lesion, variables including clinical target volume (CTV), dose and location/magnitude of hot spots were recorded. Hot spot location was stratified as either within tumor bed (CTV) or within the PTV expansion margin (PTV minus CTV). Overall survival (OS) estimated using Kaplan-Meier method. Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence (LR). Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. RESULTS: Median age and OS for all patients was 58.5 years and 16.2 months, respectively. For all targets, the median CTV was 17.53 cc, and mean max hotspot was 113%. At 1 year, cumulative incidence of RN and LR for all patients was 21.8% and 13.1%. Univariate analysis showed max hot spot (hazard ratio (HR): 3.28, p=0.045) and hot spots within PTV expansion margin of 105%, 110% and 111% predicted for RN with HRs of 3.64, 8.47, and 6.90 respectively (all p

We design and implement an intensity-modulated radiation therapy plan generation technology that effectively and efficiently optimizes beam geometry as well as beam intensities. Our approach is based on an existing linear programming-based fluence map optimization model that approximates dose-volume requirements using conditional value-at-risk (C-VaR) constraints. We show how the parameters of the C-VaR constraints can be used to control various metrics of treatment plan quality. Next, we develop an automated search strategy for parameter tuning. Finally, beam angle selection is integrated with fluence map optimization. The beam angle selection scheme employs a bicriteria scoring of beam angle geometries and a selection mechanism to choose from among the set of nondominated geometries. The overall technology is automated and generates several high-quality treatment plans satisfying dose prescription requirements in a single invocation and without human guidance. The technology has been tested on various real-patient cases with uniform success.

The objective was to evaluate the performance of a high‐definition multileaf collimator (MLC) of 2.5 mm leaf width (MLC2.5) and compare to standard 5 mm leaf width MLC (MLC5) for the treatment of intracranial lesions using dynamic conformal arcs (DCA) technique with a dedicated radiosurgery linear accelerator. Simulated cases of spherical targets were created to study solely the effect of target volume size on the performance of the two MLC systems independent of target shape complexity. In addition, 43 patients previously treated for intracranial lesions in our institution were retrospectively planned using DCA technique with MLC2.5 and MLC5 systems. The gross tumor volume ranged from 0.07 to 40.57 cm3 with an average volume of 5.9 cm3. All treatment parameters were kept the same for both MLC‐based plans. The plan evaluation was performed using figures of merits (FOM) for a rapid and objective assessment on the quality of the two treatment plans for MLC2.5 and MLC5. The prescription isodose surface was selected as the greatest isodose surface covering ≥95% of the target volume and delivering 95% of the prescription dose to 99% of target volume. A Conformity Index (CI) and conformity distance index (CDI) were used to quantifying the dose conformity to a target volume. To assess normal tissue sparing, a normal tissue difference (NTD) was defined as the difference between the volume of normal tissue receiving a certain dose utilizing MLC5 and the volume receiving the same dose using MLC2.5. The CI and normal tissue sparing for the simulated spherical targets were better with the MLC2.5 as compared to MLC5. For the clinical patients, the CI and CDI results indicated that the MLC2.5 provides better treatment conformity than MLC5 even at large target volumes. The CI's range was 1.15 to 2.44 with a median of 1.59 for MLC2.5 compared to 1.60–2.85 with a median of 1.71 for MLC5. Improved normal tissue sparing was also observed for MLC2.5 over MLC5, with the NTD always positive, indicating improvement, and ranging from 0.1 to 8.3 for normal tissue receiving 50% (NTV50), 70% (NTV70) and 90% (NTV90) of the prescription dose. The MLC2.5 has a dosimetric advantage over the MLC5 in Linac‐based radiosurgery using DCA method for intracranial lesions, both in treatment conformity and normal tissue sparing when target shape complexity increases. PACS number: 87.56J‐, 87.56 jk

e14091Background: Allele-specific copy number analysis of tumors (ASCAT) is a quantitative method of assessing copy number variations that accounts for non-aberrant cell contributions and tumor plo...

Purpose To investigate the incidence, risks, severity, and sequelae of posterior fossa syndrome (PFS) in children with medulloblastoma. Methods and Materials Between 1990 and 2007, 63 children with medulloblastoma at Emory University and Children's Healthcare of Atlanta were treated with craniectomy followed by radiation. Fifty-one patients were assigned to a standard-risk group, and 12 patients were assigned to a high-risk group. Five patients had 2 residual tumor, 4 had ≥1.5-cm 2 residual tumor, and the remainder had no residual tumor. Eleven patients had disseminated disease. Patients received craniospinal irradiation at a typical dose of 23.4 Gy or 36 Gy for standard- or high-risk disease, respectively. The posterior fossa was given a total dose of 54 or 55.8 Gy. Nearly all patients received chemotherapy following cooperative group protocols. Results Median follow-up was 7 years. PFS developed in 18 patients (29%). On univariate analysis, brainstem invasion, midline tumor location, younger age, and the absence of radiographic residual tumor were found to be predictors of PFS; the last two variables remained significant on multivariate analysis. From 1990 to 2000 and from 2001 to 2007, the proportions of patients with no radiographic residual tumor were 77% and 94%, respectively. During the same eras, the proportions of patients with PFS were 17% and 39%. Only 4 patients had complete recovery at last follow-up. Conclusions The incidence of PFS increased in the latter study period and is proportional to more aggressive surgery. Children with midline tumors exhibiting brainstem invasion are at increased risk. With the increased incidence of PFS and the permanent morbidity in many patients, the risks and benefits of complete tumor removal in all patients need to be reexamined.

Purpose To assess local control and treatment-related toxicity of single-modality radiation therapy (RT) in the treatment of imaging-defined meningiomas. Methods and Materials The records of Emory University School of Medicine, Atlanta, GA, were reviewed between 1985 and 2003. We identified 41 patients with 42 meningiomas treated with RT alone for lesions diagnosed on imaging alone. No patients received a histologic diagnosis. Patients in whom there was uniform agreement that the tumor represented a meningioma were accepted for therapy. Of the patients, 22 were treated with stereotactic radiosurgery (SRS), 11 with fractionated stereotactic radiotherapy (FSR), and 9 with three-dimensional conformal therapy (3DCRT). The median doses of SRS, FSR, and 3DCRT were 14 Gy, 50.4 Gy, and 52.2 Gy, respectively. Results Median follow-up was 60 months. Of 42 meningiomas, 39 were locally controlled. The 8-year actuarial local control rate by Kaplan-Meier methods was 94%. One failure occurred 6 months after 3DCRT, a second at 34 months after FSR, and a third at 125 months after SRS. A temporary symptomatic radiation-related neurologic sequela developed in 1 patient treated with SRS. No fatal treatment complications occurred. The 8-year rate for actuarial freedom from complication survival by Kaplan-Meier methods was 97%. Conclusions RT alone is an attractive alternative to surgery for imaging-defined meningiomas without significant mass effect. It offers local control comparable to surgical resection with minimal morbidity. RT should be considered as a viable alternative to surgery for tumors in various locations.