Stereotactic radiosurgery versus stereotactic radiotherapy in the management of intracranial meningiomas: a systematic review and meta-analysis.

OBJECTIVEStereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have been used as a primary treatment or adjuvant to resection in the management of intracranial meningiomas (ICMs). The aim of this analysis is to compare the safety and long-term efficacy of SRS and SRT in patients with primary or recurrent ICMs.METHODSA systematic review of the literature comparing SRT and SRS in the same study was conducted using PubMed, the Cochrane Library, Google Scholar, and EMBASE from January 1980 to December 2018. Randomized controlled trials, case-control studies, and cohort studies (prospective and retrospective) analyzing SRS versus SRT for the treatment of ICMs in adult patients (age > 16 years) were included. Pooled and subgroup analyses were based on the fixed-effect model.RESULTSA total of 1736 patients from 12 retrospective studies were included. The treatment modality used was: 1) SRS (n = 306), including Gamma Knife surgery (n = 36), linear accelerator (n = 261), and CyberKnife (n = 9); or 2) SRT (n = 1430), including hypofractionated SRT (hFSRT, n = 268) and full-fractionated SRT (FSRT, n = 1162). The median age of patients at the time of treatment was 59 years. The median follow-up duration after treatment was 35.5 months. The median tumor volumes at the time of treatment with SRS, hFSRT, and FSRT were 2.84 cm3, 5.45 cm3, and 12.75 cm3, respectively. The radiographic tumor control at last follow-up was significantly worse in patients who underwent SRS than SRT (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.27-0.82, p = 0.007) with 7% less volume of tumor shrinkage (OR 0.93, 95% CI 0.61-1.40, p = 0.72). Compared to SRS, the radiographic tumor control was better achieved by FSRT (OR 0.46, 95% CI 0.26-0.80, p = 0.006) than by hFSRT (OR 0.81, 95% CI 0.21-3.17, p = 0.76). Moreover, SRS leads to a significantly higher risk of clinical neurological worsening during follow-up (OR 2.07, 95% CI 1.06-4.06, p = 0.03) and of immediate symptomatic edema (OR 4.58, 95% CI 1.67-12.56, p = 0.003) with respect to SRT. SRT could produce a better progression-free survival at 4-10 years compared to SRS, but this was not statistically significant (p = 0.29).CONCLUSIONSSRS and SRT are both safe options in the management of ICMs. However, SRT carries a better radiographic tumor control rate and a lower incidence of posttreatment symptomatic worsening and symptomatic edema, with respect to SRS. However, further prospective studies are still needed to validate these results.

Image-guided stereotactic radiosurgery for treatment of spinal hemangioblastoma.

OBJECTIVE Stereotactic radiosurgery (SRS) has been an attractive treatment option for hemangioblastomas, especially for lesions that are surgically inaccessible and in patients with von Hippel-Lindau (VHL) disease and multiple lesions. Although there has been a multitude of studies examining the utility of SRS in intracranial hemangioblastomas, SRS has only recently been used for spinal hemangioblastomas due to technical limitations. The purpose of this study is to provide a long-term evaluation of the effectiveness of image-guided radiosurgery in halting tumor progression and providing symptomatic relief for spinal hemangioblastomas. METHODS Between 2001 and 2011, 46 spinal hemangioblastomas in 28 patients were treated using the CyberKnife image-guided radiosurgery system at the authors' institution. Fourteen of these patients also had VHL disease. The median age at treatment was 43.5 years (range 19-85 years). The mean prescription radiation dose to the tumor periphery was 21.6 Gy (range 15-35 Gy). The median tumor volume was 0.264 cm3 (range 0.025-70.9 cm3). Tumor response was evaluated on serial, contrast-enhanced CT and MR images. Clinical response was evaluated by clinical and imaging evaluation. RESULTS The mean follow-up for the cohort was 54.3 months. Radiographic follow-up was available for 19 patients with 34 tumors; 32 (94.1%) tumors were radiographically stable or displayed signs of regression. Actuarial control rates at 1, 3, and 5 years were 96.1%, 92.3%, and 92.3%, respectively. Clinical evaluation on follow-up was available for 13 patients with 16 tumors; 13 (81.2%) tumors in 10 patients had symptomatic improvement. No patient developed any complications related to radiosurgery. CONCLUSIONS Image-guided SRS is safe and effective for the primary treatment of spinal hemangioblastomas and is an attractive alternative to resection, especially for those with VHL disease.

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma.

The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity.

Staged-volume radiosurgery for large arteriovenous malformations: a review.

Stereotactic radiosurgery is an effective management strategy for properly selected patients with arteriovenous malformations (AVMs). However, the risk of postradiosurgical radiation-related injury is higher in patients with large AVMs. Multistaged volumetric management of large AVMs was undertaken to limit the radiation exposure to the surrounding normal brain. This strategy offers a promising method for obtaining high AVM obliteration rates with minimal normal tissue damage. The use of embolization as an adjunctive method in the treatment of large AVMs remains controversial. Unfortunately, staged-volume radiosurgery (SVR) has a number of potential pitfalls that affect the outcome. The aim of this article is to highlight the role of SVR in the treatment of large AVMs, to discuss the outcome comparing it to other treatment modalities, and to discuss the potential improvement that could be introduced to this method of treatment.

Cyst formation after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review.

OBJECTIVE Cyst formation can occasionally occur after stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs). Given the limited data regarding post-SRS cyst formation in patients with AVM, the time course, natural history, and management of this delayed complication are poorly defined. The aim of this systematic review was to determine the incidence, time course, and optimal management of cyst formation after SRS for AVMs. METHODS A literature review was performed using PubMed to identify studies reporting cyst formation in AVM patients treated with SRS. Baseline and outcomes data, including the incidence and management of post-SRS cysts, were extracted from each study that reported follow-up duration. The mean time to cyst formation was calculated from the subset of studies that reported individual patient data. RESULTS Based on pooled data from 22 studies comprising the incidence analysis, the overall rate of post-SRS cyst formation was 3.0% (78/2619 patients). Among the 26 post-SRS cyst patients with available AVM obliteration data, nidal obliteration was achieved in 20 (76.9%). Of the 64 cyst patients with available symptomatology and management data, 21 (32.8%) were symptomatic; 21 cysts (32.8%) were treated with surgical intervention, whereas the remaining 43 (67.2%) were managed conservatively. Based on a subset of 19 studies reporting individual time-to-cyst-formation data from 63 patients, the mean latency period to post-SRS cyst formation was 78 months (6.5 years). CONCLUSIONS Cyst formation is an uncommon complication after SRS for AVMs, with a relatively long latency period. The majority of post-SRS cysts are asymptomatic and can be managed conservatively, although enlarging or symptomatic cysts may require surgical intervention. Long-term follow-up of AVM patients is crucial to the appropriate diagnosis and management of post-SRS cysts.

Stereotactic radiosurgery in the treatment of parasellar meningiomas: long-term volumetric evaluation.

OBJECTIVE Parasellar meningiomas tend to invade the suprasellar, cavernous sinus, and petroclival regions, encroaching on adjacent neurovascular structures. As such, they prove difficult to safely and completely resect. Stereotactic radiosurgery (SRS) has played a central role in the treatment of parasellar meningiomas. Evaluation of tumor control rates at this location using simplified single-dimension measurements may prove misleading. The authors report the influence of SRS treatment parameters and the timing and volumetric changes of benign WHO Grade I parasellar meningiomas after SRS on long-term outcome. METHODS Patients with WHO Grade I parasellar meningiomas treated with single-session SRS and a minimum of 6 months of follow-up were selected. A total of 189 patients (22.2% males, n = 42) form the cohort. The median patient age was 54 years (range 19-88 years). SRS was performed as a primary upfront treatment for 44.4% (n = 84) of patients. Most (41.8%, n = 79) patients had undergone 1 resection prior to SRS. The median tumor volume at the time of SRS was 5.6 cm3 (0.2-54.8 cm3). The median margin dose was 14 Gy (range 5-35 Gy). The volumes of the parasellar meningioma were determined on follow-up scans, computed by segmenting the meningioma on a slice-by-slice basis with numerical integration using the trapezoidal rule. RESULTS The median follow-up was 71 months (range 6-298 months). Tumor volume control was achieved in 91.5% (n = 173). Tumor progression was documented in 8.5% (n = 16), equally divided among infield recurrences (4.2%, n = 8) and out-of-field recurrences (4.2%, n = 8). Post-SRS, new or worsening CN deficits were observed in 54 instances, of which 19 involved trigeminal nerve dysfunction and were 18 related to optic nerve dysfunction. Of these, 90.7% (n = 49) were due to tumor progression and only 9.3% (n = 5) were attributable to SRS. Overall, this translates to a 2.64% (n = 5/189) incidence of direct SRS-related complications. These patients were treated with repeat SRS (6.3%, n = 12), repeat resection (2.1%, n = 4), or both (3.2%, n = 6). For patients treated with a margin dose ≥ 16 Gy, the 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates are 100%, 100%, 95.7%, 95.7%, 95.7%, 95.7%, and 95.7%, respectively. Patients treated with a margin dose < 16 Gy, had 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates of 99.4%, 97.7%, 95.1%, 88.1%, 82.1%, 79.4%, and 79.4%, respectively. This difference was deemed statistically significant (p = 0.043). Reviewing the volumetric patient-specific measurements, the early follow-up volumetric measurements (at the 3-year follow-up) reliably predicted long-term volume changes and tumor volume control (at the 10-year follow-up) (p = 0.029). CONCLUSIONS SRS is a durable and minimally invasive treatment modality for benign parasellar meningiomas. SRS offers high rates of growth control with a low incidence of neurological deficits compared with other treatment modalities for meningiomas in this region. Volumetric regression or stability during short-term follow-up of 3 years after SRS was shown to be predictive of long-term tumor control.

Assessment of motion error for frame-based and noninvasive mask-based fixation using the Leksell Gamma Knife Icon radiosurgery system.

OBJECTIVEThe Leksell Gamma Knife Icon (GK Icon) radiosurgery system can utilize cone-beam computed tomography (CBCT) to evaluate motion error. This study compares the accuracy of frame-based and frameless mask-based fixation using the Icon system.METHODSA retrospective cohort study was conducted to evaluate patients who had undergone radiosurgery with the GK Icon system between June and December 2017. Patients were immobilized in either a stereotactic head frame or a noninvasive thermoplastic mask with stereotactic infrared (IR) camera monitoring. Setup error was defined as displacement of the skull in the stereotactic space upon setup as noted on pretreatment CBCT compared to its position in the stereotactic space defined by planning MRI for frame patients and defined as skull displacement on planning CBCT compared to its position on pretreatment CBCT for mask patients. For frame patients, the intrafractionation motion was measured by comparing pretreatment and posttreatment CBCT. For mask patients, the intrafractionation motion was evaluated by comparing pretreatment CBCT and additional CBCT obtained during the treatment. The translational and rotational errors were recorded.RESULTSData were collected from 77 patients undergoing SRS with the GK Icon. Sixty-four patients underwent frame fixation, with pre- and posttreatment CBCT studies obtained. Thirteen patients were treated using mask fixation to deliver a total of 33 treatment fractions. Mean setup and intrafraction translational and rotation errors were small for both fixation systems, within 1 mm and 1° in all axes. Yet mask fixation demonstrated significantly larger intrafraction errors than frame fixation. Also, there was greater variability in both setup and intrafraction errors for mask fixation than for frame fixation in all translational and rotational directions. Whether the GK treatment was for metastasis or nonmetastasis did not influence motion uncertainties between the two fixation types. Additionally, monitoring IR-based intrafraction motion for mask fixation-i.e., the number of treatment stoppages due to reaching the IR displacement threshold-correlated with increasing treatment time.CONCLUSIONSCompared to frame-based fixation, mask-based fixation demonstrated larger motion variations. The variability in motion error associated with mask fixation must be taken into account when planning for small lesions or lesions near critical structures.

Volume-staged versus dose-staged stereotactic radiosurgery outcomes for large brain arteriovenous malformations: a systematic review.

OBJECTIVE Several recent studies have improved our understanding of the outcomes of volume-staged (VS) and dose-staged (DS) stereotactic radiosurgery (SRS) for the treatment of large (volume > 10 cm3) brain arteriovenous malformations (AVMs). In light of these recent additions to the literature, the aim of this systematic review is to provide an updated comparison of VS-SRS and DS-SRS for large AVMs. METHODS A systematic review of the literature was performed using PubMed to identify cohorts of 5 or more patients with large AVMs who had been treated with VS-SRS or DS-SRS. Baseline data and post-SRS outcomes were extracted for analysis. RESULTS A total of 11 VS-SRS and 10 DS-SRS studies comprising 299 and 219 eligible patients, respectively, were included for analysis. The mean obliteration rates for VS-SRS and DS-SRS were 41.2% (95% CI 31.4%-50.9%) and 32.3% (95% CI 15.9%-48.8%), respectively. Based on pooled individual patient data, the outcomes for patients treated with VS-SRS were obliteration in 40.3% (110/273), symptomatic radiation-induced changes (RICs) in 13.7% (44/322), post-SRS hemorrhage in 19.5% (50/256), and death in 7.4% (24/323); whereas the outcomes for patients treated with DS-SRS were obliteration in 32.7% (72/220), symptomatic RICs in 12.2% (31/254), post-SRS hemorrhage in 10.6% (30/282), and death in 4.6% (13/281). CONCLUSIONS Volume-staged SRS appears to afford higher obliteration rates than those achieved with DS-SRS, although with a less favorable complication profile. Therefore, VS-SRS or DS-SRS may be a reasonable treatment approach for large AVMs, either as stand-alone therapy or as a component of a multimodality management strategy.

Multimodal management of arteriovenous malformations of the basal ganglia and thalamus: factors affecting obliteration and outcome.

OBJECTIVE: Arteriovenous malformations (AVMs) of the basal ganglia and thalamus are particularly difficult lesions to treat, accounting for 3%-13% of all AVMs in surgical series and 23%-44% of malformations in radiosurgery series. The goal of this study was to report the results of multimodal management of basal ganglia and thalamic AVMs and investigate the factors that influence radiographic cure and good clinical outcomes. METHODS: This study was a retrospective analysis of a prospectively maintained database of all patients treated at the authors' institution. Clinical, radiological, follow-up, and outcome data were analyzed. Univariate and multivariate analyses were conducted to explore the influence of various factors on outcome. RESULTS: The results and data analysis pertaining to 123 patients treated over 32 years are presented. In this cohort, radiographic cure was achieved in 50.9% of the patients. Seventy-five percent of patients had good clinical outcomes (stable or improved performance scores), whereas 25% worsened after treatment. Inclusion of surgery and radiosurgery independently predicted obliteration, whereas nidus diameter and volume predicted clinical outcomes. Nidus volume/diameter and inclusion of surgery predicted the optimal outcome, i.e., good clinical outcomes with lesion obliteration. CONCLUSIONS: Good outcomes are possible with multimodal treatment in these complex patients. Increasing size and, by extension, higher Spetzler-Martin grade are associated with worse outcomes. Inclusion of multiple modalities of treatment as indicated could improve the chances of radiographic cure and good outcomes.

Proceedings of the 2018 next-generation Gamma Knife research meeting.

In order to determine what areas of research are a clinical priority, a small group of young Gamma Knife investigators was invited to attend a workshop discussion at the 19th International Leksell Gamma Knife Society Meeting. Two areas of interest and the need for future radiosurgical research involving multiple institutions were identified by the young investigators working group: 1) the development of additional imaging sequences to guide the understanding, treatment, and outcome tracking of diseases such as tremor, radiation necrosis, and AVM; and 2) trials to clarify the role of hypofractionation versus single-fraction radiosurgery in the treatment of large lesions such as brain metastases, postoperative cavities, and meningiomas.

Diffusion tractography imaging-guided frameless linear accelerator stereotactic radiosurgical thalamotomy for tremor: case report.

Essential tremor and Parkinson's disease-associated tremor are extremely prevalent within the field of movement disorders. The ventral intermediate (VIM) nucleus of the thalamus has been commonly used as both a neuromodulatory and neuroablative target for the treatment of these forms of tremor. With both deep brain stimulation and Gamma Knife radiosurgery, there is an abundance of literature regarding the surgical planning, targeting, and outcomes of these methodologies. To date, there have been no reports of frameless, linear accelerator (LINAC)-based thalomotomies for tremor. The authors report the case of a patient with tremor-dominant Parkinson's disease, with poor tremor improvement with medication, who was offered LINAC-based thalamotomy. High-resolution 0.9-mm isotropic MR images were obtained, and simulation was performed via CT with 1.5-mm contiguous slices. The VIM thalamic nucleus was determined using diffusion tensor imaging (DTI)-based segmentation on FSL using probabilistic tractography. The supplemental motor and premotor areas were the cortical target masks. The authors centered their isocenter within the region of the DTI-determined target and treated the patient with 140 Gy in a single fraction. The DTI-determined target had coordinates of 14.2 mm lateral and 8.36 mm anterior to the posterior commissure (PC), and 3 mm superior to the anterior commissure (AC)-PC line, which differed by 3.30 mm from the original target determined by anatomical considerations (15.5 mm lateral and 7 mm anterior to the PC, and 0 mm superior to the AC-PC line). There was faint radiographic evidence of lesioning at the 3-month follow-up within the target zone, which continued to consolidate on subsequent scans. The patient experienced continued right upper-extremity resting tremor improvement starting at 10 months until it was completely resolved at 22 months of follow-up. Frameless LINAC-based thalamotomy guided by DTI-based thalamic segmentation is a feasible method for achieving radiosurgical lesions of the VIM thalamus to treat tremor.

Long-term tumor control following stereotactic radiosurgery for jugular paraganglioma using 3D volumetric segmentation.

OBJECTIVEThe morbidity of gross-total resection of jugular paraganglioma (JP) is often unacceptable due to the potential for irreversible lower cranial neuropathy. Stereotactic radiosurgery (SRS) has been used at the authors' institution since 1990 for the treatment of JP and other benign intracranial tumors. Conventional means of assessing tumor progression using linear measurements or elliptical approximations are imprecise due to the irregular shape and insinuating growth pattern of JP. The objective of this study was to assess long-term tumor control in these patients by using slice-by-slice 3D volumetric segmentation of serial MRI data.METHODSRadiographic data and clinical records were reviewed retrospectively at a single, tertiary-care academic referral center for patients treated from 1990 to 2017. Volumetric analyses by integration of consecutive tumor cross-sectional areas (tumor segmentation) of serial MRI data were performed. Tumor progression was defined as volumetric growth of 15% or greater over the imaging interval. Primary outcomes analyzed included survival free of radiographic and clinical progression. Secondary outcomes included new or worsened cranial neuropathy.RESULTSA total of 85 patients were treated with Gamma Knife radiosurgery (GKRS) for JP at the authors' institution over the last 27 years. Sixty patients had pretreatment and serial posttreatment contrast-enhanced MRI follow-up suitable for volumetric analysis. A total of 214 MR images were analyzed to segment tumor images in a slice-by-slice fashion to calculate integral tumor volume. The median follow-up duration was 66 months (range 7-202 months). At 5 years the tumor progression-free survival rate was 98%. Three tumors exhibited progression more than 10 years after GKRS. Estimated survival free of radiographic progression rates (95% confidence interval [CI]; n = number still at risk) at 5, 10, and 15 years following radiosurgery were 98% (95% CI 94%-100%; n = 34), 94% (95% CI 85%-100%; n = 16), and 74% (95% CI 56%-98%; n = 6), respectively. One patient with tumor progression required treatment intervention using external beam radiation therapy, constituting the only case of clinical progression. Two patients (3%) without preexisting lower cranial nerve dysfunction developed new ipsilateral vocal fold paralysis following radiosurgery.CONCLUSIONSSRS achieves excellent long-term tumor control for JP without a high risk for new or worsened cranial neuropathy when used in primary, combined modality, or recurrent settings. Long-term follow-up is critical due to the potential for late radiographic progression (i.e., more than 10 years after SRS). As none of the patients with late progression have required salvage therapy, the clinical implications of this degree of tumor growth have yet to be determined.

Does size matter? Investigating the optimal planning target volume margin for postoperative stereotactic radiosurgery to resected brain metastases.

OBJECTIVE: The 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. METHODS: Records 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. RESULTS: A 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). CONCLUSIONS: Expanding 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.

Radiosurgery in the management of brain metastasis: a retrospective single-center study comparing Gamma Knife and LINAC treatment.

OBJECTIVE The authors present a retrospective analysis of a single-center experience with treatment of brain metastases using Gamma Knife (GK) and linear accelerator (LINAC)-based radiosurgery and compare the results. METHODS From July 2010 to July 2012, 63 patients with brain metastases were treated with radiosurgery. Among them, 28 (with 83 lesions) were treated with a GK unit and 35 (with 47 lesions) with a LINAC. The primary outcome was local progression-free survival (LPFS), evaluated on a per-lesion basis. The secondary outcome was overall survival (OS), evaluated per patient. Statistical analysis included standard tests and Cox regression with shared-frailty models to account for the within-patient correlation. RESULTS The mean follow-up period was 11.7 months (median 7.9 months, range 1.7-32 months) for GK and 18.1 months (median 17 months, range 7.5-28.7 months) for LINAC. The median number of lesions per patient was 2.5 (range 1-9) in the GK group and 1 (range 1-3) in the LINAC group (p < 0.01, 2-sample t-test). There were more radioresistant lesions (e.g., melanoma) and more lesions located in functional areas in the GK group. Additional technical reasons for choosing GK instead of LINAC were limitations of LINAC movements, especially if lesions were located in the lower posterior fossa or multiple lesions were close to highly functional areas (e.g., the brainstem), precluding optimal dosimetry with LINAC. The median marginal dose was 24 Gy with GK and 20 Gy with LINAC (p < 0.01, 2-sample t-test). For GK, the actuarial LPFS rate at 3, 6, 9, 12, and 17 months was 96.96%, 96.96%, 96.96%, 88.1%, and 81.5%, remaining stable until 32 months. For LINAC the rate at 3, 6, 12, 17, 24, and 33 months was 91.5%, 91.5%, 91.5%, 79.9%, 55.5%, and 17.1% (log-rank p = 0.03). In the Cox regression with shared-frailty model, the risk of local progression in the LINAC group was almost twice that of the GK group (HR 1.92, p > 0.05). The mean OS was 16.0 months (95% CI 11.2-20.9 months) in the GK group, compared with 20.9 months (95% CI 16.4-25.3 months) in the LINAC group. Univariate and multivariate analysis showed that a lower graded prognostic assessment (GPA) score, noncontrolled systemic status at last radiological assessment, and older age were associated with lower OS; after adjustment of these covariables by Cox regression, the OS was similar in the 2 groups. CONCLUSIONS In this retrospective study comparing GK and LINAC-based radiosurgery for brain metastases, patients with more severe disease were treated by GK, including those harboring lesions of greater number, of radioresistant type, or in highly functional areas. The risk of local progression for the LINAC group was almost twice that in the GK group, although the difference was not statistically significant. Importantly, the OS rates were similar for the 2 groups, although GK was used in patients with more complex brain metastatic disease and with no other therapeutic alternative.

Stereotactic radiosurgery for trigeminal neuralgia: a systematic review.

OBJECTIVES: The aims of this systematic review are to provide an objective summary of the published literature specific to the treatment of classical trigeminal neuralgia with stereotactic radiosurgery (RS) and to develop consensus guideline recommendations for the use of RS, as endorsed by the International Society of Stereotactic Radiosurgery (ISRS). METHODS: The authors performed a systematic review of the English-language literature from 1951 up to December 2015 using the Embase, PubMed, and MEDLINE databases. The following MeSH terms were used in a title and abstract screening: "radiosurgery" AND "trigeminal." Of the 585 initial results obtained, the authors performed a full text screening of 185 studies and ultimately found 65 eligible studies. Guideline recommendations were based on level of evidence and level of consensus, the latter predefined as at least 85% agreement among the ISRS guideline committee members. RESULTS: The results for 65 studies (6461 patients) are reported: 45 Gamma Knife RS (GKS) studies (5687 patients [88%]), 11 linear accelerator (LINAC) RS studies (511 patients [8%]), and 9 CyberKnife RS (CKR) studies (263 patients [4%]). With the exception of one prospective study, all studies were retrospective.The mean maximal doses were 71.1-90.1 Gy (prescribed at the 100% isodose line) for GKS, 83.3 Gy for LINAC, and 64.3-80.5 Gy for CKR (the latter two prescribed at the 80% or 90% isodose lines, respectively). The ranges of maximal doses were as follows: 60-97 Gy for GKS, 50-90 Gy for LINAC, and 66-90 Gy for CKR.Actuarial initial freedom from pain (FFP) without medication ranged from 28.6% to 100% (mean 53.1%, median 52.1%) for GKS, from 17.3% to 76% (mean 49.3%, median 43.2%) for LINAC, and from 40% to 72% (mean 56.3%, median 58%) for CKR. Specific to hypesthesia, the crude rates (all Barrow Neurological Institute Pain Intensity Scale scores included) ranged from 0% to 68.8% (mean 21.7%, median 19%) for GKS, from 11.4% to 49.7% (mean 27.6%, median 28.5%) for LINAC, and from 11.8% to 51.2% (mean 29.1%, median 18.7%) for CKR. Other complications included dysesthesias, paresthesias, dry eye, deafferentation pain, and keratitis. Hypesthesia and paresthesia occurred as complications only when the anterior retrogasserian portion of the trigeminal nerve was targeted, whereas the other listed complications occurred when the root entry zone was targeted. Recurrence rates ranged from 0% to 52.2% (mean 24.6%, median 23%) for GKS, from 19% to 63% (mean 32.2%, median 29%) for LINAC, and from 15.8% to 33% (mean 25.8%, median 27.2%) for CKR. Two GKS series reported 30% and 45.3% of patients who were pain free without medication at 10 years. CONCLUSIONS: The literature is limited in its level of evidence, with only one comparative randomized trial (1 vs 2 isocenters) reported to date. At present, one can conclude that RS is a safe and effective therapy for drug-resistant trigeminal neuralgia. A number of consensus statements have been made and endorsed by the ISRS.

Three-stage Gamma Knife treatment for metastatic brain tumors larger than 10 cm3: a 2-institute study including re-analyses of earlier results using competing risk analysis.

OBJECTIVEThe results of 3-stage Gamma Knife treatment (3-st-GK-Tx) for relatively large brain metastases have previously been reported for a series of patients in Chiba, Japan (referred to in this study as the C-series). In the current study, the authors reappraised, using a competing risk analysis, the efficacy and safety of 3-st-GK-Tx by comparing their experience with that of the C-series.METHODSThis was a retrospective cohort study. Among 1767 patients undergoing GK radiosurgery for brain metastases at Mito Gamma House during the 2005-2015 period, 78 (34 female, 44 male; mean age 65 years, range 35-86 years) whose largest tumor was > 10 cm3, treated with 3-st-GK-Tx, were studied (referred to in this study as the M-series). The target volumes were covered with a 50% isodose gradient and irradiated with a peripheral dose of 10 Gy at each procedure. The interval between procedures was 2 weeks. Because competing risk analysis had not been employed in the published C-series, the authors reanalyzed the previously published data using this method.RESULTSThe overall median survival time after 3-st-GK-Tx was 8.3 months (95% CI 5.6-12.0 months) in the M-series and 8.6 months (95% CI 5.5-10.6 months) in the C-series (p = 0.41). Actuarial survival rates at the 6th and 12th post-3-st-GK-Tx months were, respectively, 55.1% and 35.2% in the M-series and 62.5% and 26.4% in the C-series (HR 1.175, 95% CI 0.790-1.728, p = 0.42). Cumulative incidences at the 12th post-3-st-GK-Tx, determined by competing risk analyses, of neurological deterioration (14.2% in C-series vs 12.8% in M-series), neurological death (7.2% vs 7.7%), local recurrence (4.8% vs 6.2%), repeat SRS (25.9% vs 18.0%), and SRS-related complications (2.3% vs 5.1%) did not differ significantly between the 2 series.CONCLUSIONSThere were no significant differences in post-3-st-GK-Tx results between the 2 series in terms of overall survival times, neurological death, maintained neurological status, local control, repeat SRS, and SRS-related complications. The previously published results (C-series) are considered to be validated by the M-series results.

Multimodal treatment of parasagittal meningiomas: a single-center experience.

OBJECTIVE Treatment of parasagittal meningiomas is still considered a challenge in modern microsurgery. The use of microsurgical resection, radiosurgery, or a microsurgery-radiosurgery combination treatment strategy is often debated. The aim of this study was to evaluate the treatment of parasagittal meningioma and provide evidence that a multimodal approach reduces complication rates and achieves good tumor control rates. METHODS The authors retrospectively reviewed long-term follow-up data on 117 patients who had been treated for parasagittal meningiomas at their institution between 1993 and 2013. Treatment included microsurgery, Gamma Knife radiosurgery (GKRS), and radiotherapy. RESULTS The median tumor volume prior to the first microsurgical resection was largest in the microsurgery-radiosurgery combination treatment group. Invasion of the superior sagittal sinus was significantly associated with a Simpson Grade IV resection and subsequent radiosurgery treatment. The Simpson resection grade did not influence time to progression or recurrence in benign meningioma cases. Complete sinus occlusion was followed by microsurgical resection of the occluded sinus, by tumor resection without resection of the sinus, or by GKRS. Histopathology revealed WHO Grade I tumors in most patients. However, a high percentage (33%) of atypical or malignant meningiomas were diagnosed after the last microsurgical resection. The time to recurrence or progression after microsurgery was significantly longer in patients with WHO Grade I meningiomas than in those with Grade II or III meningiomas. At follow-up, tumor control rates after GKRS were 91% for presumed meningioma, 85% for benign meningioma, 71% for atypical meningioma, and 38% for malignant meningioma. CONCLUSIONS A multimodal treatment approach to parasagittal meningiomas reduces the rate of complications. Thus, microsurgery, radiotherapy, and radiosurgery are complementary treatment options. Gamma Knife radiosurgery is safe and effective in patients with meningiomas invading the superior sagittal sinus. The procedure can be part of a multimodal treatment plan or administered as a single treatment in well-selected patients.

Quality of life is maintained using Gamma Knife radiosurgery: a prospective study of a brain metastases patient cohort.

OBJECTIVE Gamma Knife radiosurgery (GKRS) is increasingly used in the management of brain metastases (BMs), but few studies have evaluated how GKRS impacts quality of life (QOL). The aim of this study was to monitor QOL as the primary end point following GKRS in a patient cohort with BM. METHODS The study included 97 consecutive patients with 1-6 BMs treated with GKRS between May 2010 and September 2011. QOL was assessed at baseline and at 1, 3, 6, 9, and 12 months postoperatively using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire with the brain cancer subscale (BRCS) questionnaire. Factors predicting QOL were identified by mixed linear regression analyses. Local control and toxicity were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and the European Organisation for Research and Treatment/Radiation Therapy Oncology Group (EORTC/RTOG) criteria of late effects, respectively. RESULTS Compliance was high from baseline (97%) to 12-month follow-up (78%). Mean BRCS scores remained high during follow-up: they improved in 66% of patients and remained unchanged in 6% at 9 months. Local control (p = 0.018), improved symptoms (p = 0.005), and stable extracerebral disease (p = 0.001) correlated with high QOL-BRCS score. High baseline recursive partitioning analysis class predicted improved QOL (p = 0.031), whereas high Karnofsky Performance Scale score (p = 0.017), asymptomatic BMs (p = 0.001), and no cognitive deficits (p = 0.033) or seizures (p = 0.040) predicted high, stable QOL-BRCS during the 12-month follow-up. CONCLUSIONS QOL remained stable for up to 12 months following GKRS for the total cohort. High QOL was reported if local control occurred, cerebral symptoms improved/stabilized, or the need for steroids declined, which all reflected successful GKRS. Conversely, low QOL accompanied progression of intra- and extracerebral disease. Based on the study findings, GKRS appears to be a safe and effective treatment option for patients with BMs.

Changing practice patterns of Gamma Knife versus linear accelerator-based stereotactic radiosurgery for brain metastases in the US.

OBJECTIVE: Single-fraction stereotactic radiosurgery (SRS) is a crucial component in the management of limited brain metastases from non-small cell lung cancer (NSCLC). Intracranial SRS has traditionally been delivered using a frame-based Gamma Knife (GK) platform, but stereotactic modifications to the linear accelerator (LINAC) have made an alternative approach possible. In the absence of definitive prospective trials comparing the efficacy and toxicities of treatment between the 2 techniques, nonclinical factors (such as technology accessibility, costs, and efficiency) may play a larger role in determining which radiosurgery system a facility may choose to install. To the authors' knowledge, this study is the first to investigate national patterns of GK SRS versus LINAC SRS use and to determine which factors may be associated with the adoption of these radiosurgery systems. METHODS: The National Cancer Data Base was used to identify patients > 18 years old with NSCLC who were treated with single-fraction SRS to the brain between 2003 and 2011. Patients who received "SRS not otherwise specified" or who did not receive a radiotherapy dose within the range of 12-24 Gy were excluded to reduce the potential for misclassification. The chi-square test, t-test, and multivariable logistic regression analysis were used to compare potential demographic, clinicopathologic, and health care system predictors of GK versus LINAC SRS use, when appropriate. RESULTS: This study included 1780 patients, among whom 1371 (77.0%) received GK SRS and 409 (23.0%) underwent LINAC SRS. Over time, the proportion of patients undergoing LINAC SRS steadily increased, from 3.2% in 2003 to 30.8% in 2011 (p < 0.001). LINAC SRS was adopted more rapidly by community versus academic facilities (overall 29.2% vs 17.2%, p < 0.001). On multivariable analysis, 4 independent predictors of increased LINAC SRS use emerged, including year of diagnosis in 2008-2011 versus 2003-2007 (adjusted OR [AOR] 2.04, 95% CI 1.52-2.73, p < 0.001), community versus academic facility type (AOR 2.04, 95% CI 1.60-2.60, p < 0.001), non-West versus West geographic location (AOR 4.50, 95% CI 2.87-7.09, p < 0.001), and distance from cancer reporting facility of < 20 versus ≥ 20 miles (AOR 1.57, 95% CI 1.21-2.04, p = 0.001). CONCLUSIONS: GK remains the most commonly used single-fraction SRS modality for NSCLC brain metastases in the US. However, LINAC-based SRS has been rapidly disseminating in the past decade, especially in the community setting. Wide geographic variation persists in the distribution of GK and LINAC SRS cases. Further comparative effectiveness research will be needed to evaluate the impact of these shifts on SRS-related toxicities, local control, and survival, as well as treatment costs and efficiency.

Dosimetric characterization of hypofractionated Gamma Knife radiosurgery of large or complex brain tumors versus linear accelerator-based treatments.

OBJECTIVE Noninvasive Gamma Knife (GK) platforms, such as the relocatable frame and on-board imaging, have enabled hypofractionated GK radiosurgery of large or complex brain lesions. This study aimed to characterize the dosimetric quality of such treatments against linear accelerator-based delivery systems that include the CyberKnife (CK) and volumetric modulated arc therapy (VMAT). METHODS Ten patients treated with VMAT at the authors' institution for large brain tumors (> 3 cm in maximum diameter) were selected for the study. The median prescription dose was 25 Gy (range 20-30 Gy) in 5 fractions. The median planning target volume (PTV) was 9.57 cm3 (range 1.94-24.81 cm3). Treatment planning was performed using Eclipse External Beam Planning V11 for VMAT on the Varian TrueBeam system, Multiplan V4.5 for the CyberKnife VSI System, and Leksell GammaPlan V10.2 for the Gamma Knife Perfexion system. The percentage of the PTV receiving at least the prescription dose was normalized to be identical across all platforms for individual cases. The prescription isodose value for the PTV, conformity index, Paddick gradient index, mean and maximum doses for organs at risk, and normal brain dose at variable isodose volumes ranging from the 5-Gy isodose volume (V5) to the 15-Gy isodose volume (V15) were compared for all of the cases. RESULTS The mean Paddick gradient index was 2.6 ± 0.2, 3.2 ± 0.5, and 4.3 ± 1.0 for GK, CK, and VMAT, respectively (p < 0.002). The mean V15 was 7.5 ± 3.7 cm3 (range 1.53-13.29 cm3), 9.8 ± 5.5 cm3 (range 2.07-18.45 cm3), and 16.1 ± 10.6 cm3 (range 3.58-36.53 cm3) for GK, CK, and VMAT, respectively (p ≤ 0.03, paired 2-tailed t-tests). However, the average conformity index was 1.18, 1.12, and 1.21 for GK, CK, and VMAT, respectively (p > 0.06). The average prescription isodose values were 52% (range 47%-69%), 60% (range 46%-68%), and 88% (range 70%-94%) for GK, CK, and VMAT, respectively, thus producing significant variations in dose hot spots among the 3 platforms. Furthermore, the mean V5 values for GK and CK were similar (p > 0.79) at 71.9 ± 36.2 cm3 and 73.3 ± 31.8 cm3, respectively, both of which were statistically lower (p < 0.01) than the mean V5 value of 124.6 ± 67.1 cm3 for VMAT. CONCLUSIONS Significantly better near-target normal brain sparing was noted for hypofractionated GK radiosurgery versus linear accelerator-based treatments. Such a result supports the use of a large number of isocenters or confocal beams for the benefit of normal tissue sparing in hypofractionated brain radiosurgery.