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Purpose: The present study assesses the safety and efficacy of stereotactic radiosurgery (SRS) versus observation for Koos grade 1 and 2 vestibular schwannoma (VS), benign tumors affecting hearing and neurological function., Methods and Materials: This multicenter study analyzed data from Koos grade 1 and 2 VS patients managed with SRS (SRS group) or observation (observation group). Propensity score matching balanced patient demographics, tumor volume, and audiometry. Outcomes measured were tumor control, serviceable hearing preservation, and neurological outcomes., Results: In 125 matched patients in each group with a 36-month median follow-up (P = .49), SRS yielded superior 5- and 10-year tumor control rates (99% CI, 97.1%-100%, and 91.9% CI, 79.4%-100%) versus observation (45.8% CI, 36.8%-57.2%, and 22% CI, 13.2%-36.7%; P < .001). Serviceable hearing preservation rates at 5 and 9 years were comparable (SRS 60.4% CI, 49.9%-73%, vs observation 51.4% CI, 41.3%-63.9%, and SRS 27% CI, 14.5%-50.5%, vs observation 30% CI, 17.2%-52.2%; P = .53). SRS were associated with lower odds of tinnitus (OR = 0.39, P = .01), vestibular dysfunction (OR = 0.11, P = .004), and any cranial nerve palsy (OR = 0.36, P = .003), with no change in cranial nerves 5 or 7 (P > .05). Composite endpoints of tumor progression and/or any of the previous outcomes showed significant lower odds associated with SRS compared with observation alone (P < .001)., Conclusions: SRS management in matched cohorts of Koos grade 1 and 2 VS patients demonstrated superior tumor control, comparable hearing preservation rates, and significantly lower odds of experiencing neurological deficits. These findings delineate the safety and efficacy of SRS in the management of this patient population., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiation necrosis (RN) secondary to stereotactic radiosurgery is a significant cause of morbidity. The optimal management of corticosteroid-refractory brain RN remains unclear. Our objective was to summarize the literature specific to efficacy and toxicity of treatment paradigms for patients with symptomatic corticosteroid-refractory RN and to provide consensus guidelines for grading and management of RN on behalf of the International Stereotactic Radiosurgery Society. A systematic review of articles pertaining to treatment of RN with bevacizumab, laser interstitial thermal therapy (LITT), surgical resection, or hyperbaric oxygen therapy was performed. The primary composite outcome was clinical and/or radiologic stability/improvement (ie, proportion of patients achieving improvement or stability with the given intervention). Proportions of patients achieving the primary outcome were pooled using random weighted-effects analysis but not directly compared between interventions. Twenty-one articles were included, of which only 2 were prospective studies. Thirteen reports were relevant for bevacizumab, 5 for LITT, 5 for surgical resection and 1 for hyperbaric oxygen therapy. Weighted effects analysis revealed that bevacizumab had a pooled symptom improvement/stability rate of 86% (95% CI 77%-92%), pooled T2 imaging improvement/stability rate of 93% (95% CI 87%-98%), and pooled T1 postcontrast improvement/stability rate of 94% (95% CI 87%-98%). Subgroup analysis showed a statistically significant improvement favoring treatment with low-dose (below median, ≤7.5 mg/kg every 3 weeks) versus high-dose bevacizumab with regards to symptom improvement/stability rate (P = .02) but not for radiologic T1 or T2 changes. The pooled T1 postcontrast improvement/stability rate for LITT was 88% (95% CI 82%-93%), and pooled symptom improvement/stability rate for surgery was 89% (95% CI 81%-96%). Toxicity was inconsistently reported but was generally low for all treatment paradigms. Corticosteroid-refractory RN that does not require urgent surgical intervention, with sufficient noninvasive diagnostic testing that favors RN, can be treated medically with bevacizumab in carefully selected patients as a strong recommendation. The role of LITT is evolving as a less invasive image guided surgical modality; however, the overall evidence for each modality is of low quality. Prospective head-to-head comparisons are needed to evaluate the relative efficacy and toxicity profile among treatment approaches., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting., Methods and Materials: Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration., Results: Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm 3 ; (2) 20 cm 3 ≥ V12 Gy ≥ 12 cm 3 ; (3) V12 Gy > 20 cm 3 . In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm 3 ), 10.3% (20 cm 3 ≥ V12 Gy ≥ 12 cm 3 ), and 12.6% (V12 Gy > 20 cm 3 ); the 2-year rates were 7.5% (V12 Gy < 12 cm 3 ), 13.8% (20 cm 3 ≥ V12 Gy ≥ 12 cm 3 ), and 15.4% (V12 Gy > 20 cm 3 ) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm 3 ), 8.9% (20 cm 3 ≥ V12 Gy ≥ 12 cm 3 ), and 10.3% (V12 Gy > 20 cm 3 ); the 2-year rates were 4.4% (V12 Gy < 12 cm 3 ), 12.4% (20 cm 3 ≥ V12 Gy ≥ 12 cm 3 ), and 13.1% (V12 Gy > 20 cm 3 ; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA., Conclusions: The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Brain metastases represent a major indication for stereotactic radiosurgery (SRS), but further study is needed regarding repeat SRS (SRS2) after local or marginal recurrence after prior SRS (SRS1). We report local tumor control (LC) after SRS2 and identify predictors of radiation necrosis (RN) and symptomatic RN (SRN)., Methods and Materials: Patients had biopsy-proven non-small cell lung cancer and at least 1 brain metastasis previously treated with SRS. SRS2 was performed from 2015 to 2020 and required overlap of the prescription isodose lines with those from SRS1. Patients treated with preoperative SRS were excluded. Primary endpoints were LC by Response Assessment in Neuro-oncology criteria, RN, and SRN., Results: From 8 institutions, 102 patients with 123 treated lesions were included. SRS2 was performed at a median 12 months after SRS1. SRS2 delivered a median 18 Gy (interquartile range [IQR], 16-18) margin dose to the 50% (IQR, 50%-70%) isodose line, maximum dose of 30.5 Gy (IQR, 25.0-36.0), and V12Gy of 3.38 cm 3 (IQR, 0.83-7.64). One-year and 2-year LC were 79% and 72%, respectively. Local tumor control was improved with tumor volume ≤1 cm 3 (P < .005). There were 25 (20%) cases of RN and 9 (7%) cases of SRN. For SRS1 and SRS2, SRN rates were higher with maximum doses ≥40 Gy or SRS2 V12Gy >9 cm 3 (P < .025 for each). SRS1 and SRS2 maximum dose ≥40 Gy was also predictive of increased RN (P < .05 for each). Prior immunotherapy was not predictive of RN or SRN., Conclusions: Repeat SRS afforded a high rate of local tumor control and a low rate of SRN. At SRS2, V12Gy ≤9 cm 3 and maximum dose <40 Gy may reduce the risks of RN and SRN. These results are most applicable to lesions with approximately 1 cm 3 volume and 1-year interval between SRS courses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This study assesses a large multi-institutional database to present the outcomes of World Health Organization grade 2 meningiomas treated with stereotactic radiosurgery (SRS). We also compare the 3-year progression-free survival (PFS) to that reported in the Radiation Therapy Oncology Group 0539 phase 2 cooperative group meningioma trial., Methods and Materials: From an international, multicenter group, data were collected for grade 2 meningioma patients treated with SRS for demonstrable tumor from 1994 to 2019. Statistical methods used included the Kaplan-Meier method, Cox proportional hazards analysis, and recursive partitioning analysis., Results: Two hundred thirty-three patients treated at 12 institutions were included. Patients presented at a median age of 60 years (range, 13-90), and many had at least 2 prior resections (30%) or radiation therapy (22%). Forty-eight percent of patients had prior gross total resection. At SRS, the median treatment volume was 6.1 cm 3 (0.1-97.6). A median 15 Gy (10-30) was delivered to a median percent isodose of 50 (30-80), most commonly in 1 fraction (95%). A model was developed using recursive partitioning analysis, with one point attributed to age >50 years, treatment volume >11.5 cm 3 , and prior radiation therapy or multiple surgeries. The good-prognostic group (score, 0-1) had improved PFS (P < .005) and time to local failure (P < .005) relative to the poor-prognostic group (score, 2-3). Age >50 years (hazard ratio = 1.85 [95% confidence interval, 1.09-3.14]) and multiple prior surgeries (hazard ratio = 1.80 [1.09-2.99]) also portended reduced PFS in patients without prior radiation therapy. Two hundred eighteen of 233 patients in this study qualified for the high-risk group of Radiation Therapy Oncology Group 0539, and they demonstrated similar outcomes (3-year PFS: 53.9% vs 58.8%). The good-prognostic group of SRS patients demonstrated slightly improved outcomes (3-year PFS: 63.1% vs 58.8%)., Conclusions: SRS should be considered in carefully selected patients with atypical meningiomas. We suggest the use of our good-prognostic group to optimize patient selection, and we strongly encourage the initiation of a clinical trial to prospectively validate these outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Multifraction (MF) stereotactic radiosurgery (SRS) purportedly reduces radionecrosis risk over single-fraction (SF) SRS in the treatment of large brain metastases. The purpose of the current work is to compare local control (LC) and radionecrosis rates of SF-SRS and MF-SRS in the definitive (SF-SRS D and MF-SRS D ) and postoperative (SF-SRS P and MF-SRS P ) settings., Methods and Materials: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had "large" brain metastases (Group A: 4-14 cm 3 , or about 2-3 cm in diameter; Group B: >14 cm 3 , or about >3 cm in diameter); 1-year LC and/or rates of radionecrosis were reported; radiosurgery was administered definitively or postoperatively. Random effects meta-analyses using fractionation scheme and size as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size and fractionation on the summary estimate, where the null hypothesis was rejected for P < .05., Results: Twenty-four studies were included, published between 2008 and 2017, with 1887 brain metastases. LC random effects estimate at 1 year was 77.6% for Group A/SF-SRS D and 92.9% for Group A/MF-SRS D (P = .18). LC random effects estimate at 1 year was 77.1% for Group B/SF-SRS D and 79.2% for Group B/MF-SRS D (P = .76). LC random effects estimate at 1 year was 62.4% for Group B/SF-SRS P and 85.7% for Group B/MF-SRS P (P = .13). Radionecrosis incidence random effects estimate was 23.1% for Group A/SF-SRS D and 7.3% for Group A/MF-SRS D (P = .003). Radionecrosis incidence random effects estimate was 11.7% for Group B/SF-SRS D and 6.5% for Group B/MF-SRS D (P = .29). Radionecrosis incidence random effects estimate was 7.3% for Group B/SF-SRS P and 7.5% for Group B/MF-SRS P (P = .85). Metaregression assessing 1-year LC and radionecrosis as a continuous function of increasing tumor volume was not statistically significant., Conclusions: Treatment for large brain metastases with MF-SRS regimens may offer a relative reduction of radionecrosis while maintaining or improving relative rates of 1-year LC compared with SF-SRS. These findings are hypothesis-generating and require validation by ongoing and planned prospective clinical trials., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To determine the magnitude and reason for discrepancies between frame- and cone beam computed tomography (CBCT)-determined stereotactic coordinates, we reviewed frame-based Gamma Knife radiosurgery procedures in which CBCT was performed before treatment., Methods and Materials: Clinical and treatment documentation was reviewed for 150 frame placements for which stereotactic coordinates were defined via both frame and fiducials on computed tomography imaging and CBCT. Treatment planning system-reported rotational and translational differences and standard deviations (SDs) between frame-based and CBCT-based stereotactic coordinates were recorded. Potential clinical predictors for increased differences were collected. Multiple linear regressions were performed to evaluate for associations with increased translations and rotations., Results: The absolute mean of the measured pitch, yaw, and roll shifts was 0.14 degrees (range -0.71-0.63 degrees, SD 0.19 degrees), 0.16 degrees (range -0.50 to 0.83 degrees, SD 0.21 degrees), and 0.12 degrees (range 0.37-0.51 degrees, SD 0.15 degrees), respectively. The absolute mean of the measured shifts in the left-right, anteroposterior, and superior-inferior direction was 0.29 mm (range -1.29 to 0.82 mm, SD 0.35 mm), 0.24 mm (range -0.59 to 0.33 mm, SD 0.19 mm), and 0.24 mm (range -0.69 to 0.91 mm, SD 0.27 mm), respectively. Three cases (2.0%) exceeded 1 mm in translational difference, all in the left-right direction (1.05, 1.13, and 1.29 mm). Lower Karnofsky Performance Scale status was associated with greater translational differences (vector magnitude, P = .023) and rotation (pitch, P = .044; yaw, P = .002). Usage of longer total pin length (sum of all 4 fixation pin lengths) was associated with increased rotation but not with translation (P < .001 and P = .56, respectively)., Conclusions: CBCT imaging in this cohort of frame-based cases suggests that the discrepancy in stereotactic coordinates is less than 1 mm or degree in most cases. Low Karnofsky Performance Scale status and longer total pin length correlate with larger differences between frame-defined and CBCT-defined stereotactic coordinates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To compare and describe the time to endocrine remission and new hypopituitarism among patients with growth hormone (GH) and adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas after radiosurgery, controlling for several known prognostic factors., Methods and Materials: An institutional review board-approved, institutional retrospective analysis of patients with GH- and ACTH-secreting pituitary adenomas was performed, with matching for patient sex, age at radiosurgery, interval between the last resection and radiosurgery, use of previous radiation therapy, whole sella treatment, suprasellar extension, cavernous sinus invasion, and margin dose. Endocrine remission was defined as a normal serum insulin-like growth factor-1 (GH secreting) or a normal 24-hour urine-free cortisol (ACTH secreting) level without suppressive medications. Endocrine remission and the incidence of new hypopituitarism after single-fraction radiosurgery were recorded and compared between the 2 groups., Results: The data from 242 patients were evaluated, 121 with GH-secreting tumors and 121 with ACTH-secreting tumors. Of the 242 patients, 75% had cavernous sinus invasion and 10% had suprasellar extension at radiosurgery. The median radiosurgical marginal dose was 25 Gy to the 50% isodose line between each group. After multivariable adjustment, the factors associated with an increased time to endocrine remission included patient age (hazard ratio [HR] 1.016; P = .023), cavernous sinus invasion (HR 1.793; P = .004), and the presence of acromegaly (HR 2.912; P < .001). The incidence of new hypopituitarism developing after stereotactic radiosurgery was 29% and did not appreciably differ by adenoma subtype (P = .180)., Conclusions: After radiosurgery, patients with ACTH-secreting tumors achieved endocrine remission sooner than did those with GH-secreting tumors. These results provide insight into the relative tumor biology and disease course after radiosurgery that will serve to further improve clinical outcomes and patient treatment in the future., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To propose contouring guidelines based on consensus contours generated by 10 international experts for cavity stereotactic radiosurgery (SRS), an emerging treatment option after surgical resection of brain metastases. No guidelines for contouring the surgical cavity volume have been previously reported., Methods and Materials: Ten postoperative completely resected cases with varying clinical scenarios and locations within the brain were selected. For each case, 10 experts independently contoured the surgical cavity clinical target volume (CTV). All the contours were analyzed, and agreement was calculated using the simultaneous truth and performance level estimation (STAPLE) with the kappa statistic. A follow-up survey was also completed by each investigator to summarize their contouring rationale for a number of different clinical scenarios. The results from the survey and the consensus STAPLE contours were both summarized to establish contouring guidelines., Results: A high level of agreement was found between the expert CTV contours (mean sensitivity 0.75, mean specificity 0.98), and the mean kappa was 0.65. The agreement was statistically significant at P<.001 for all cases. From these results and analyses of the survey answers, the recommendations for CTV include fusion of the preoperative magnetic resonance imaging scan to aid in volume delineation; contouring the entire surgical tract regardless of the preoperative location of the tumor; extension of the CTV 5 to 10 mm along the dura overlying the bone flap to account for microscopic disease extension in cases with preoperative dural contact; and a margin of ≤5 mm into the adjacent sinus when preoperative venous sinus contact was present., Conclusions: Consensus contouring guidelines for postoperative completely resected cavity SRS treatment were established using expert contours and clinical practice. However, in the absence of clinical data supporting these recommendations, these guidelines serve as a baseline for further study and refinement., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To pool data across multiple institutions internationally and report on the cumulative experience of brainstem stereotactic radiosurgery (SRS)., Methods and Materials: Data on patients with brainstem metastases treated with SRS were collected through the International Gamma Knife Research Foundation. Clinical, radiographic, and dosimetric characteristics were compared for factors prognostic for local control (LC) and overall survival (OS) using univariate and multivariate analyses., Results: Of 547 patients with 596 brainstem metastases treated with SRS, treatment of 7.4% of tumors resulted in severe SRS-induced toxicity (grade ≥3, increased odds with increasing tumor volume, margin dose, and whole-brain irradiation). Local control at 12 months after SRS was 81.8% and was improved with increasing margin dose and maximum dose. Overall survival at 12 months after SRS was 32.7% and impacted by age, gender, number of metastases, tumor histology, and performance score., Conclusions: Our study provides additional evidence that SRS has become an option for patients with brainstem metastases, with an excellent benefit-to-risk ratio in the hands of experienced clinicians. Prior whole-brain irradiation increases the risk of severe toxicity in brainstem metastasis patients undergoing SRS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy., Methods and Materials: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewed and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling., Results: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003)., Conclusions: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider., (Copyright © 2015 Elsevier Inc. All rights reserved.)