Two-stage radiosurgery for large brain metastases: a systematic review and meta-analysis of clinical outcomes.

OBJECTIVE: Brain metastases (BMs) are the most common intracranial tumors. In several cases, they present as large masses, which are related to a worse prognosis and more complex therapeutic alternatives. Staged radiosurgery is reported to achieve local control with minimal radiation-related adverse events in BMs. However, no methodological consensus has been achieved in its use for large brain metastases (LBMs; > 2 cm). Therefore, the authors aimed to determine the effectiveness and safety of 2-stage Gamma Knife radiosurgery (GKRS) for LBMs, in order to optimize patients' postoperative course. METHODS: A systematic review of available literature was run in PubMed/MEDLINE, Scopus, Web of Science, Cochrane (OvidSP), and Google Scholar for works published up to December 14, 2022. Nonrandomized clinical trials, case series, and cohort studies were included. The risk of bias was assessed using the Risk of Bias in Nonrandomized Studies-of Interventions (ROBINS-I) and Joanna Briggs Institute tools. Pooled mean difference and rates estimates were calculated by a random-effects model meta-analysis. The degree of heterogeneity was expressed using the I2 statistic. A subgroup analysis was performed. Ultimately, the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment. RESULTS: Fourteen studies met the eligibility criteria (cohorts, case series, and nonrandomized clinical trials), including 958 patients. A total pooled mean volume reduction of 6.27 cm3 (95% CI 5.67-6.88 cm3) and 54.36% (95% CI 39.92%-68.79%) after 2-stage GKRS was reported. Pooled rates of complete response (44.63%; 95% CI 26.50%-64.31%), neurological mortality (16.19%; 95% CI 7.68%-30.98%), and all-cause mortality (47.92%; 95% CI 28.04%-68.49%) were calculated. Overall certainty of evidence ranged from very low to moderate. CONCLUSIONS: Two-stage GKRS is an effective and safe approach for the treatment of LBMs. Nevertheless, the lack of available literature and the weak methodological approaches used determine a low to very low certainty of evidence and cannot provide robust evidence to recommend this intervention. Therefore, it is necessary to conduct higher-quality primary studies.

Fractionated versus staged gamma knife radiosurgery for mid-to-large brain metastases: a propensity score-matched analysis.

PURPOSE: To compare treatment results between fractionated gamma knife radiosurgery (f-GKRS) and staged gamma knife radiosurgery (s-GKRS) for mid-to-large brain metastases (BMs). METHODS: We retrospectively analyzed data of patients with medium (4-10 mL) to large (> 10 mL) BMs who underwent s-GKRS or f-GKRS between March 2008 and September 2022. Patients were treated with (i) s-GKRS before May 2018 and (ii) f-GKRS after May 2018. Patients who underwent follow-up magnetic resonance imaging at least once were enrolled. Case-matched studies were conducted by applying propensity score matching to minimize treatment selection bias and potential confounding. Local control (LC) was set as the primary endpoint and overall survival (OS) as the secondary endpoint. RESULTS: This study included 129 patients with 136 lesions and 70 patients with 78 lesions who underwent s-GKRS and f-GKRS, respectively. Overall, 124 lesions (62 lesions in each group) were selected in the case-matched group. No differences were observed in the 6-month and 1-year cumulative incidences of LC failure between the s-GKRS and f-GKRS groups (15.6% vs. 15.9% at 6 months and 25.6% vs. 25.6% at 1 year; p = 0.617). One-year OS rates were 62.6% (95% confidence interval [CI]: 45.4-75.7%) and 73.9% (95% CI: 58.8-84.2%) in the s-GKRS and f-GKRS groups, respectively. The post-GKRS median survival time was shorter in the s-GKRS group than in the f-GKRS group (17 vs. 36 months), without significance (p = 0.202). CONCLUSIONS: This is the first study to compare f-GKRS and s-GKRS in large BMs. Fractionation is as effective as staged GKRS for treating mid-to-large BMs.

Dose-staged Gamma Knife radiosurgery for meningiomas: A retrospective study in a single center.

Objective: This study aimed to study the efficiency and safety of a dose-staged Gamma Knife radiosurgery strategy for large meningiomas or meningiomas close to important nerve structures. Methods: This study evaluates the outcome of a prospectively accrued series of 71 consecutive patients with meningiomas treated with staged dose-fractionated Gamma Knife radiosurgery. The average peripheral doses for the first and second fractions were 9.0 ± 0.9 Gy (8-12 Gy) and 8.6 ± 0.7 Gy (range, 7-10 Gy), respectively. The interval between fractions was 6.1 ± 1.9 months (range, 3-12 months). The median follow-up time was 36 months (12-96 months). Results: During the follow-up period after the second fraction, 97.2% achieved tumor control in our series. A total of 2 patients exhibited local recurrence at 30 and 60 months after the second fraction, respectively. No treatment-related complications or new long-term neurological dysfunctions were reported. MRIs observed slightly or moderately increased peritumoral edema in six patients, but no specific neurological complaints are attributed to this finding. Conclusion: This study investigates the efficiency and safety of dose-staged Gamma Knife radiosurgery as an alternative option for meningiomas that were large in volume, adjacent to crucial structures, or in patients with contraindications to craniotomy.

Evaluation of Biological Effective Dose in Gamma Knife Staged Stereotactic Radiosurgery for Large Brain Metastases.

Objective: Gamma knife (GK) staged stereotactic radiosurgery (Staged-SRS) has become an effective treatment option for large brain metastases (BMs); however, it has been challenging to evaluate the total dose because of tumor shrinkage between two staged sessions. This study aims to evaluate total biological effective dose (BED) in Staged-SRS, and to compare the BED with those in single-fraction SRS (SF-SRS) and hypo-fractionated SRS (HF-SRS). Methods: Patients treated with GK Staged-SRS at a single institution were retrospectively included. The dose delivered in two sessions of Staged-SRS was summed using the deformable image registration. Each patient was replanned for SF-SRS and HF-SRS. The total BEDs were computed using the linear-quadratic model. Tumor BED98% and brain V84Gy2, equivalent to V12Gy in SF-SRS, were compared between SF-SRS, HF-SRS, and Staged-SRS plans with the Wilcoxon test. Results: Twelve patients with 24 BMs treated with GK Staged-SRS were identified. We observed significant differences (p < 0.05) in tumor BED98% but comparable brain V84Gy2 (p = 0.677) between the Staged-SRS and SF-SRS plans. No dosimetric advantages of Staged-SRS over HF-SRS were observed. Tumor BED98% in the HF-SRS plans were significantly higher than those in the Staged-SRS plans (p < 0.05). Despite the larger PTVs, brain V84Gy2 in the HF-SRS plans remained lower (p < 0.05). Conclusion: We presented an approach to calculate the composite BEDs delivered to both tumor and normal brain tissue in Staged-SRS. Compared to SF-SRS, Staged-SRS delivers a higher dose to tumor but maintains a comparable dose to normal brain tissue. Our results did not show any dosimetric advantages of Staged-SRS over HF-SRS.

Intracranial arteriovenous malformations.

The treatment of arteriovenous malformations (AVMs) has evolved over the last 10 years. It is now possible to see that obliteration continues for up to 10 years and that the final obliteration rate may be between 85% and 90%. Improved imaging has made the treatment more efficient and has reduced the complications. It is possible to treat larger AVMs in a single session than was previously thought possible without increases in the complication rates. In addition, treatments of larger lesions can be staged. The use of 3D rotating angiography produces remarkable images which can be imported into GammaPlan. On the other hand efforts are ongoing to avoid the need for digital subtraction angiography, which would make the treatment a lot more comfortable.

Staged radiosurgery alone versus postoperative cavity radiosurgery for patients with midsize-to-large brain metastases: a propensity score matching analysis.

OBJECTIVE: The authors investigated and compared the results of staged stereotactic radiosurgery (S-SRS) alone and those of postoperative cavity SRS (C-SRS) for patients with midsize-to-large brain metastases (BMs). METHODS: Patients with BMs who had undergone S-SRS or C-SRS during the period from 2010 to 2020 were retrospectively identified from an institutional database. The two treatment groups were generated by propensity score matching (PSM; match ratio 2:1) based on 13 potential prognostic covariates: sex, age, Karnofsky Performance Status, type of primary cancer, timing of BM diagnosis, extracranial disease status, driver mutations, molecular target therapy, neurological symptoms, number of BMs, location of BMs treated with S-SRS or C-SRS, maximal tumor or cavity volume, and cumulative intracranial tumor volume. Patient survival and control of intracranial disease were compared between the S-SRS and C-SRS groups using time-dependent analyses taking into account competing events. RESULTS: In total, 110 patients in the S-SRS group and 62 in the C-SRS group were selected by PSM. In the S-SRS group, the median interval between the two radiosurgical sessions was 21 days, and the median total prescription dose was 28 Gy at 50%. In the C-SRS group, the median time from surgery to C-SRS was 16 days, and the median prescription dose delivered to the surgical cavity was 15 Gy at 55%. At the time point of data set fixation, 129 patients had died, 43 were alive, and none had been lost to follow-up. The 2-year survival rates for the S-SRS and C-SRS groups after the initial intervention were 33% and 37% and the median survival times were 14.8 and 17.5 months, respectively (p = 0.33). The 2-year cumulative neurological mortality rates were 11% and 9%, respectively (p = 0.65). The 2-year local failure rates were 32% and 12% (p = 0.036) and the 2-year distant recurrence rates were 55% and 58%, respectively (p = 0.53). The 2-year leptomeningeal disease development rates were 9% and 25%, respectively (p = 0.007). CONCLUSIONS: The present study revealed no significant difference in overall survival or cumulative neurological mortality between the S-SRS and C-SRS groups. The local control failure rate was significantly higher in the S-SRS group, whereas the incidence of leptomeningeal disease development was significantly higher in the C-SRS group.

Volume-Staged Radiosurgery for Large Arteriovenous Malformation: Retrospective Analysis of 19 Cases.

Introduction The effectiveness of Gamma Knife surgery (GKS) for small arteriovenous malformations (AVMs) is well known. However, for large AVMs, the prescribed dose should be decreased to reduce the risk of radiation damage, but it leads to a decrease in nidus obliteration rates. Therefore, it is very difficult to achieve complete obliteration of large AVMs in a single treatment, and methods using multiple irradiation such as volume-staged stereotactic radiosurgery (VS-SRS) have been suggested. We retrospectively reviewed our results of VS-SRS for large AVMs to assess the efficacy of VS-SRS. Methods Nineteen patients with AVMs of ≥10 ml and who consented to VS-SRS were treated by this surgical strategy and retrospectively analyzed. We excluded AVMs that were too large such as those >40 cc to avoid severe radiation damage. The components were divided mainly in the vertical direction, and each component was irradiated with a marginal dose of 18 Gy. Each irradiation was performed at intervals of 3-6 months, and the components with main feeders were irradiated first, and the components that included the main drainer were irradiated last. We tried to keep V18 to <10 ml if possible. The follow-up after GKS was performed by MRI every 6 months, and cerebral angiography was performed to confirm complete nidus obliteration, but if the patient refused, it was judged on the basis of MRI findings. Results Nineteen patients with a mean age of 40.2 years underwent VS-SRS. Each compartment was irradiated at 3--16 month (median, 3 months) intervals. The mean initial AVM volume was 19 ± 5.6 ml. Fourteen patients received two-stage radiosurgery and five received three-stage radiosurgery. The median target volume was 9.1 ml at stage 1, 9.0 ml at stage 2, and 10.1 ml at stage 3. The median margin dose was 18 Gy at each stage. The mean follow-up after the last stage of radiosurgery was 3.9 (1-11.4) years. Complete obliteration was confirmed by angiography in six patients, and by magnetic resonance angiography in one patient. The cumulative obliteration rates were 30.7% and 58.2% at 3 and 5 years following VS-SRS, respectively. The cumulative hemorrhage rates were 7.1% and 22.1% at 3 and 5 years, respectively. MRI showed T2-weighted prolongation in 15 patients (78.9%). Of these 15 patients, four were symptomatic (epilepsy in all) and two underwent surgical removal of symptomatic expanding hematomas. Conclusions In our experience, VS-SRS offers a viable treatment strategy in patients with large AVMs. Further optimization of the dose and volume at each stage is required.

Safety and efficacy of upfront stereotactic radiosurgery for brain metastases with high cumulative intracranial tumor volume (> 7 ml): analysis of 233 consecutive patients.

BACKGROUND: The cumulative intracranial tumor volume (CITV) has recently been suggested to be a more relevant predictive factor for patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS). We aimed to investigate the feasibility of upfront SRS for patients with BM having a high CITV, i.e., exceeding 7 ml. METHODS: Two hundred thirty-three consecutive patients with BM having a CITV > 7 ml who underwent SRS as first-line treatment from 2011 to 2019 were retrospectively identified. The overall survival (OS) and intracranial disease control rates were analyzed. Multivariate proportional hazards models were used to identify prognostic factors associated with treatment outcome. Toxicity and salvage therapy were also investigated. RESULTS: The median OS was 8.7 months (95% confidence interval: 7.1-10.4), and 6-month and 1-year OS rates were 60 and 40%, respectively. Systemic anticancer therapy (hazard ratio (HR): 0.45, p < 0.001), female sex (HR: 0.61, p = 0.001), synchronous SRS (HR: 0.57, p = 0.003), number of BM (HR: 1.04, p = 0.008), controlled extracranial disease (HR: 0.56, p = 0.009), Karnofsky performance status (HR: 0.87, p = 0.015), and staged SRS (HR: 0.71, p = 0.037) were found to be factors independently associated with OS. Post-SRS toxicities of CTCAE grades 3, 4, and 5 were observed in 14, 5, and 1 patient, respectively. As salvage management, repeat SRS, whole brain radiotherapy, and surgical resection were required for 84, 16, and 10 patients, respectively, CONCLUSIONS: With vigilant surveillance and appropriate salvage management, upfront SRS alone can be considered as a relatively safe and effective treatment strategy even for BM with CITV > 7 ml.

Volume-Staged Radiosurgery for Large Arteriovenous Malformation.

Large arteriovenous malformations (AVMs) are challenges in management because of outcomes and adverse affects. Volume-staged radiosurgery has been an appropriate approach when removal resection and embolization are not recommended. A 53-year-old gentleman was diagnosed with a large intracranial AVM with persistent headache and short-term seizure. Brain magnetic resonance and angiograph showed a bulky volume of AVM nidus. Removal resection and embolization were not recommended because of high risk of adverse affects. The patient was treated by volume-staged radiosurgery. One year post-treatment, obliteration for right internal carotid artery was completed. Volume-staged radiosurgery is a potential treatment option for large AVM with controlled and obliteration efficacy, especially to AVMs which are not appropriate for removal surgery and embolization.

Single- versus 2-session Gamma Knife surgery for symptomatic midsize brain metastases: a propensity score-matched analysis.

OBJECTIVE: Two-session Gamma Knife surgery (GKS) has recently been demonstrated to be an effective and less-invasive alternative for large brain metastases not treatable by microsurgical resection. This raises the clinical question of whether the 2-session GKS strategy further improves treatment outcomes for patients with symptomatic midsize brain metastases (2-10 cm3) as compared to single-session GKS. The present study aimed to compare the local therapeutic effects and toxicities of single-session and 2-session GKS for treating these lesions. METHODS: Patients with focal neurological deficits attributable to midsize brain metastases who underwent upfront GKS during the period from 2010 to 2018 were retrospectively identified from an institutional database. Patients for whom both post-GKS imaging studies and neurological evaluations from outpatient visits were available were eligible. Using propensity score-matching (PSM) analysis, unique matched pairs which had a similar likelihood of receiving 2-session GKS were generated. The main outcome measure was a composite of imaging and/or neurological worsening of the lesion of interest. Functional improvement and overall survival (OS) were also compared between the 2 treatment arms. RESULTS: In total, 219 cancer patients with 252 symptomatic midsize brain metastases were eligible. Of these 252 tumors, 176 and 76 were treated with single- and 2-session GKS, respectively. After PSM, 68 pairs of tumors were obtained. The Gray test showed that 2-session GKS achieved a longer local progression-free interval than single-session GKS (1-year local control rate: 84% vs 53%; HR 0.31, 95% CI 0.16-0.63, p = 0.001). Two-session GKS was also associated with greater functional improvement in KPS scores (mean 18.3 ± 14.6 vs 12.8 ± 14.1, p = 0.040). The median OS did not differ significantly between single- and 2-session GKS (15.6 vs 24.7 months; HR 0.69, 95% CI 0.44-1.10, p = 0.11). CONCLUSIONS: Two-session GKS achieved more durable local tumor control and greater functional improvement than single-session GKS for patients with symptomatic midsize brain metastases, although there was no OS advantage.

Volume-staged Gamma Knife radiosurgery for orbital venous malformations.

OBJECTIVEThis article is a preliminary evaluation of the efficacy of volume-staged Gamma Knife radiosurgery (GKRS) in the treatment of patients with orbital venous malformations (OVMs).METHODSTwenty patients with moderate to large OVMs were treated with volume-staged GKRS between March 2005 and October 2015. The series included 8 male and 12 female patients with an average age of 22.5 years (range 9-45 years). The diagnoses were confirmed intraoperatively and at pathological examination in 14 cases and presumed in accordance with clinical and imaging findings in 6 cases. The median OVM volume was 12.2 cm3 (range 7.1-34.6 cm3). The median interval between stages was 10 months (range 6-12 months). The tumor margin dose for each stage ranged from 11.0 to 13.5 Gy. The median duration of follow-up was 45.5 months (range 18-98 months).RESULTSPeriodically scheduled MRI studies demonstrated evidence of a significant reduction of the original OVM volume in all cases. Visual acuity (VA) was preserved in 18 cases (90%). Five patients (25%) experienced vision improvement of varying degrees, and 13 (65%) experienced long-term preservation of VA at their pre-GKRS level. Deterioration in VA was observed in only 2 cases (10%). MRI demonstrated OVM regression after treatment in all cases, and all patients were found to have reduction of exophthalmos after volume-staged GKRS. Follow-up MRI revealed recurrence in only 1 case (5%). Three patients (15%) developed transient conjunctival edema.CONCLUSIONSThis retrospective investigation indicates that volume-staged GKRS provides an effective management option in selected patients with OVMs, providing excellent visual outcomes. The study adds substantial support for volume-staged GKRS as a major treatment for OVMs.

Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases ≥ 2 cm.

OBJECTIVE Stereotactic radiosurgery (SRS) is the primary modality for treating brain metastases. However, effective radiosurgical control of brain metastases ≥ 2 cm in maximum diameter remains challenging and is associated with suboptimal local control (LC) rates of 37%-62% and an increased risk of treatment-related toxicity. To enhance LC while limiting adverse effects (AEs) of radiation in these patients, a dose-dense treatment regimen using 2-staged SRS (2-SSRS) was used. The objective of this study was to evaluate the efficacy and toxicity of this treatment strategy. METHODS Fifty-four patients (with 63 brain metastases ≥ 2 cm) treated with 2-SSRS were evaluated as part of an institutional review board-approved retrospective review. Volumetric measurements at first-stage stereotactic radiosurgery (first SSRS) and second-stage SRS (second SSRS) treatments and on follow-up imaging studies were determined. In addition to patient demographic data and tumor characteristics, the study evaluated 3 primary outcomes: 1) response at first follow-up MRI, 2) time to local progression (TTP), and 3) overall survival (OS) with 2-SSRS. Response was analyzed using methods for binary data, TTP was analyzed using competing-risks methods to account for patients who died without disease progression, and OS was analyzed using conventional time-to-event methods. When needed, analyses accounted for multiple lesions in the same patient. RESULTS Among 54 patients, 46 (85%) had 1 brain metastasis treated with 2-SSRS, 7 patients (13%) had 2 brain metastases concurrently treated with 2-SSRS, and 1 patient underwent 2-SSRS for 3 concurrent brain metastases ≥ 2 cm. The median age was 63 years (range 23-83 years), 23 patients (43%) had non-small cell lung cancer, and 14 patients (26%) had radioresistant tumors (renal or melanoma). The median doses at first and second SSRS were 15 Gy (range 12-18 Gy) and 15 Gy (range 12-15 Gy), respectively. The median duration between stages was 34 days, and median tumor volumes at the first and second SSRS were 10.5 cm3 (range 2.4-31.3 cm3) and 7.0 cm3 (range 1.0-29.7 cm3). Three-month follow-up imaging results were available for 43 lesions; the median volume was 4.0 cm3 (range 0.1-23.1 cm3). The median change in volume compared with baseline was a decrease of 54.9% (range -98.2% to 66.1%; p < 0.001). Overall, 9 lesions (14.3%) demonstrated local progression, with a median of 5.2 months (range 1.3-7.4 months), and 7 (11.1%) demonstrated AEs (6.4% Grade 1 and 2 toxicity; 4.8% Grade 3). The estimated cumulative incidence of local progression at 6 months was 12% ± 4%, corresponding to an LC rate of 88%. Shorter TTP was associated with greater tumor volume at baseline (p = 0.01) and smaller absolute (p = 0.006) and relative (p = 0.05) decreases in tumor volume from baseline to second SSRS. Estimated OS rates at 6 and 12 months were 65% ± 7% and 49% ± 8%, respectively. CONCLUSIONS 2-SSRS is an effective treatment modality that resulted in significant reduction of brain metastases ≥ 2 cm, with excellent 3-month (95%) and 6-month (88%) LC rates and an overall AE rate of 11%. Prospective studies with larger cohorts and longer follow-up are necessary to assess the durability and toxicities of 2-SSRS.

Radiosurgery for intracranial meningiomas: A systematic review and meta-analysis.

BACKGROUND: Radiosurgery(RS), both in single and multiple sessions, have been performed for intracranial meningiomas. Different aspects are still controversial on this field. The aim of this systematic review is to summarize the current literature on long-term efficacy and safety of RS for meningiomas. METHODS: Online databases were searched for studies published until April 2015. The primary outcomes were disease control and progression-free-survival(PFS). The secondary outcomes were symptom control and radiation-induced toxicity. RESULTS: The estimate of disease control rate ranged from 87.0% to 100.0% at 5 years and from 67.0% to 100.0% at 10 years. The PFS rate ranged 78.0%-98.9% and 53.1%-97.2% at 5 and 10 years, respectively. The overall symptom control was 92.3%, the overall toxicity was 8.1%. CONCLUSIONS: RS can be considered a safe and effective treatment. Efforts are needed in standardizing the definition of local and symptom control and toxicity in order to properly compare different treatment schedules.

Volume-staged radiosurgery for large arteriovenous malformations: an evolving paradigm.

OBJECT Large arteriovenous malformations (AVMs) remain difficult to treat, and ideal treatment parameters for volume-staged stereotactic radiosurgery (VS-SRS) are still unknown. The object of this study was to compare VS-SRS treatment outcomes for AVMs larger than 10 ml during 2 eras; Era 1 was 1992-March 2004, and Era 2 was May 2004-2008. In Era 2 the authors prospectively decreased the AVM treatment volume, increased the radiation dose per stage, and shortened the interval between stages. METHODS All cases of VS-SRS treatment for AVM performed at a single institution were retrospectively reviewed. RESULTS Of 69 patients intended for VS-SRS, 63 completed all stages. The median patient age at the first stage of VS-SRS was 34 years (range 9-68 years). The median modified radiosurgery-based AVM score (mRBAS), total AVM volume, and volume per stage in Era 1 versus Era 2 were 3.6 versus 2.7, 27.3 ml versus 18.9 ml, and 15.0 ml versus 6.8 ml, respectively. The median radiation dose per stage was 15.5 Gy in Era 1 and 17.0 Gy in Era 2, and the median clinical follow-up period in living patients was 8.6 years in Era 1 and 4.8 years in Era 2. All outcomes were measured from the first stage of VS-SRS. Near or complete obliteration was more common in Era 2 (log-rank test, p = 0.0003), with 3- and 5-year probabilities of 5% and 21%, respectively, in Era 1 compared with 24% and 68% in Era 2. Radiosurgical dose, AVM volume per stage, total AVM volume, era, compact nidus, Spetzler-Martin grade, and mRBAS were significantly associated with near or complete obliteration on univariate analysis. Dose was a strong predictor of response (Cox proportional hazards, p < 0.001, HR 6.99), with 3- and 5-year probabilities of near or complete obliteration of 5% and 16%, respectively, at a dose < 17 Gy versus 23% and 74% at a dose ≥ 17 Gy. Dose per stage, compact nidus, and total AVM volume remained significant predictors of near or complete obliteration on multivariate analysis. Seventeen patients (25%) had salvage surgery, SRS, and/or embolization. Allowing for salvage therapy, the probability of cure was more common in Era 2 (log-rank test, p = 0.0007) with 5-year probabilities of 0% in Era 1 versus 41% in Era 2. The strong trend toward improved cure in Era 2 persisted on multivariate analysis even when considering mRBAS (Cox proportional hazards, p = 0.055, HR 4.01, 95% CI 0.97-16.59). The complication rate was 29% in Era 1 compared with 13% in Era 2 (Cox proportional hazards, not significant). CONCLUSIONS VS-SRS is an option to obliterate or downsize large AVMs. Decreasing the AVM treatment volume per stage to ≤ 8 ml with this technique allowed a higher dose per fraction and decreased time to response, as well as improved rates of near obliteration and cure without increasing complications. Reducing the volume of these very large lesions can facilitate a surgical approach for cure.