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Justin S. Smith, Ian F. Parney, Kathleen R. Lamborn, Michael W. McDermott, Penny K. Sneed and Susan M. Chang

Object

This study was designed to assess the presentation, management, and outcome of cases involving patients who had a supratentorial glioma that subsequently progressed in the posterior fossa (PF).

Methods

The authors performed a retrospective chart review of adult patients treated between 1997 and 2005 for supratentorial gliomas that progressed in the PF. The 29 patients with PF progression in this study were relatively young (median age of 34 years at original presentation). Twenty of these patients presented with symptoms. The symptoms were typically nonspecific to this population, at times leading to delays in diagnosis. Overall, these symptoms resolved in eight patients (40%) and progressed or remained unchanged in 12 (60%). Patients treated with more than 5000 cGy of radiation administered to the PF were more likely to have symptom resolution than those who received any other form of treatment, including reduced doses of radiation (p = 0.004). The patients treated with higher doses also survived significantly longer after PF progression (univariate analysis, p = 0.01, and after adjusting for tumor grade, p = 0.04).

Conclusions

Patients with PF progression of supratentorial infiltrative gliomas may benefit from treatment, and the authors recommend more than 5000 cGy of radiation to the PF if prior radiotherapy ports and doses allow.

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Elias Dagnew, Jeffrey Kanski, Michael W. McDermott, Penny K. Sneed, Christopher McPherson, John C. Breneman and Ronald E. Warnick

Object

Whole-brain radiotherapy (WBRT) after resection of a single brain metastasis can cause long-term radiation toxicity. The authors evaluated the efficacy of resection and placement of 125I seeds (without concomitant WBRT) for newly diagnosed single brain metastases.

Methods

In a retrospective review from two institutions (1997–2003), 15 women and 11 men (mean age 55 years) with single brain metastasis underwent gross-total resection and placement of permanent low-activity 125I seeds. Primary systemic cancer sites varied. Patients were monitored clinically and radiographically. With neuroimaging evidence of local recurrence or new distant metastasis, further treatment was administered at the physician's discretion. By the median follow-up evaluation (12 months), the local tumor control rate was 96%. Distant metastases occurred in three patients within 3 months, suggesting synchronous metastasis, and in six patients more than 3 months after treatment, indicating metachronous metastasis. Treatment in these cases included radio-surgery in seven patients, WBRT in two, and resection together with 125I seed placement in one. Two patients who suffered radiation necrosis required operative intervention (lesion diameter > 3 cm, total activity > 40 mCi). All 26 patients who had been treated using resection and placement of 125I seeds had a stable or an improved Karnofsky Performance Scale score. At the last review, nine of 16 living patients showed no evidence of treatment failure. The median actuarial survival rate was 17.8 months (Kaplan–Meier method).

Conclusions

Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumor control. Local control and patient survival rates were at least as good as those reported for resection combined with WBRT. Although the authors noted a higher incidence of distant metastases compared with that reported in other studies of initial WBRT, these metastases were generally well controlled with a combination of surgery, stereotactic radiosurgery, and, less often, WBRT. Twenty-four patients (92%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

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Fred G. Barker II, Michael D. Prados, Susan M. Chang, Philip H. Gutin, Kathleen R. Lamborn, David A. Larson, Mary K. Malec, Michael W. McDermott, Penny K. Sneed, William M. Wara and Charles B. Wilson

✓ To determine the value of radiographically assessed response to radiation therapy as a predictor of survival in patients with glioblastoma multiforme (GBM), the authors studied a cohort of 301 patients who were initially treated according to uniform clinical protocols. All patients had newly diagnosed supratentorial GBM and underwent the maximum safe resection followed by external-beam radiation treatment (60 Gy in standard daily fractions or 70.4 Gy in twice-daily fractions of 160 cGy). The radiation response and survival rates were assessable in 222 patients. The extent of resection and the immediate response to radiation therapy were highly correlated with survival, both in a univariate analysis and after correction for age and Karnofsky performance scale (KPS) score in a multivariate Cox model (p < 0.001 for radiation response and p = 0.04 for extent of resection). A subgroup analysis suggested that neuroimaging obtained within 3 days after surgery served as a better baseline for assessment of radiation response than images obtained later. Imaging obtained within 3 days after completion of a course of radiation therapy also provided valid radiation response scores. The impact of the radiographically assessed radiation response on survival time was comparable to that of age or KPS score. This information is easily obtained early in the course of the disease, may be of value for individual patients, and may also have implications for the design and analysis of trials of adjuvant therapy for GBM, including volume-dependent therapies such as radiosurgery or brachytherapy.

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William C. Chen, Stephen T. Magill, Ashley Wu, Harish N. Vasudevan, Olivier Morin, Manish K. Aghi, Philip V. Theodosopoulos, Arie Perry, Michael W. McDermott, Penny K. Sneed, Steve E. Braunstein and David R. Raleigh

OBJECTIVE

The goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and overall survival in patients undergoing primary resection of atypical meningioma, and to identify predictive factors to inform patient selection for adjuvant RT.

METHODS

One hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis.

RESULTS

The median patient age and imaging follow-up were 57 years (interquartile range [IQR] 45–67 years) and 4.4 years (IQR 1.8–7.5 years), respectively. Gross-total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1–0.9, p = 0.02) and MIB1 labeling index (LI) ≤ 7% (RR 0.4, 95% CI 0.1–0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1–0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1–0.4, p < 0.001), MIB1 LI ≤ 7% (RR 0.2, 95% CI 0.1–0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3–18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI ≤ 7% (RR 0.1, 95% CI 0.003–0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI ≤ 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04–0.7, p = 0.009) and ≤ 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03–0.4, p = 0.002) were predictive on MVA for local progression.

CONCLUSIONS

Adjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although independent validation is required, the authors’ results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma.

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David R. Raleigh, Zachary A. Seymour, Bryan Tomlin, Philip V. Theodosopoulos, Mitchel S. Berger, Manish K. Aghi, Sarah E. Geneser, Devan Krishnamurthy, Shannon E. Fogh, Penny K. Sneed and Michael W. McDermott

OBJECTIVE

Stereotactic radiosurgery (SRS) with or without whole-brain radiotherapy can be used to achieve local control (> 90%) for small brain metastases after resection. However, many brain metastases are unsuitable for SRS because of their size or previous treatment, and whole-brain radiotherapy is associated with significant neurocognitive morbidity. The purpose of this study was to investigate the efficacy and toxicity of surgery and iodine-125 (125I) brachytherapy for brain metastases.

METHODS

A total of 95 consecutive patients treated for 105 brain metastases at a single institution between September 1997 and July 2013 were identified for this analysis retrospectively. Each patient underwent MRI followed by craniotomy with resection of metastasis and placement of 125I sources as permanent implants. The patients were followed with serial surveillance MRIs. The relationships among local control, overall survival, and necrosis were estimated by using the Kaplan-Meier method and compared with results of log-rank tests and multivariate regression models.

RESULTS

The median age at surgery was 59 years (range 29.9–81.6 years), 53% of the lesions had been treated previously, and the median preoperative metastasis volume was 13.5 cm3 (range 0.21–76.2 cm3). Gross-total resection was achieved in 81% of the cases. The median number of 125I sources implanted per cavity was 28 (range 4–93), and the median activity was 0.73 mCi (range 0.34–1.3 mCi) per source. A total of 476 brain MRIs were analyzed (median MRIs per patient 3; range 0–22). Metastasis size was the strongest predictor of cavity volume and shrinkage (p < 0.0001). Multivariable regression modeling failed to predict the likelihood of local progression or necrosis according to metastasis volume, cavity volume, or the rate of cavity remodeling regardless of source activity or previous SRS. The median clinical follow-up time in living patients was 14.4 months (range 0.02–13.6 years), and crude local control was 90%. Median overall survival extended from 2.1 months in the shortest quartile to 62.3 months in the longest quartile (p < 0.0001). The overall risk of necrosis was 15% and increased significantly for lesions with a history of previous SRS (p < 0.05).

CONCLUSIONS

Therapeutic options for patients with large or recurrent brain metastases are limited. Data from this study suggest that resection with permanent 125I brachytherapy is an effective strategy for achieving local control of brain metastasis. Although metastasis volume significantly influences resection cavity size and remodeling, volumetric parameters do not seem to influence local control or necrosis. With careful patient selection, this treatment regimen is associated with minimal toxicity and can result in long-term survival for some patients.

▪ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective case series; evidence: Class IV.

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William C. Chen, Stephen T. Magill, Ashley Wu, Harish N. Vasudevan, Olivier Morin, Manish K. Aghi, Philip V. Theodosopoulos, Arie Perry, Michael W. McDermott, Penny K. Sneed, Steve E. Braunstein and David R. Raleigh

OBJECTIVE

The goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and overall survival in patients undergoing primary resection of atypical meningioma, and to identify predictive factors to inform patient selection for adjuvant RT.

METHODS

One hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis.

RESULTS

The median patient age and imaging follow-up were 57 years (interquartile range [IQR] 45–67 years) and 4.4 years (IQR 1.8–7.5 years), respectively. Gross-total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1–0.9, p = 0.02) and MIB1 labeling index (LI) ≤ 7% (RR 0.4, 95% CI 0.1–0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1–0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1–0.4, p < 0.001), MIB1 LI ≤ 7% (RR 0.2, 95% CI 0.1–0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3–18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI ≤ 7% (RR 0.1, 95% CI 0.003–0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI ≤ 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04–0.7, p = 0.009) and ≤ 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03–0.4, p = 0.002) were predictive on MVA for local progression.

CONCLUSIONS

Adjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although independent validation is required, the authors’ results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma.

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Penny K. Sneed, Joe Mendez, Johanna G. M. Vemer-van den Hoek, Zachary A. Seymour, Lijun Ma, Annette M. Molinaro, Shannon E. Fogh, Jean L. Nakamura and Michael W. McDermott

OBJECT

The authors sought to determine the incidence, time course, and risk factors for overall adverse radiation effect (ARE) and symptomatic ARE after stereotactic radiosurgery (SRS) for brain metastases.

METHODS

All cases of brain metastases treated from 1998 through 2009 with Gamma Knife SRS at UCSF were considered. Cases with less than 3 months of follow-up imaging, a gap of more than 8 months in imaging during the 1st year, or inadequate imaging availability were excluded. Brain scans and pathology reports were reviewed to ensure consistent scoring of dates of ARE, treatment failure, or both; in case of uncertainty, the cause of lesion worsening was scored as indeterminate. Cumulative incidence of ARE and failure were estimated with the Kaplan-Meier method with censoring at last imaging. Univariate and multivariate Cox proportional hazards analyses were performed.

RESULTS

Among 435 patients and 2200 brain metastases evaluable, the median patient survival time was 17.4 months and the median lesion imaging follow-up was 9.9 months. Calculated on the basis of 2200 evaluable lesions, the rates of treatment failure, ARE, concurrent failure and ARE, and lesion worsening with indeterminate cause were 9.2%, 5.4%, 1.4%, and 4.1%, respectively. Among 118 cases of ARE, approximately 60% were symptomatic and 85% occurred 3–18 months after SRS (median 7.2 months). For 99 ARE cases managed without surgery or bevacizumab, the probabilities of improvement observed on imaging were 40%, 57%, and 76% at 6, 12, and 18 months after onset of ARE. The most important risk factors for ARE included prior SRS to the same lesion (with 20% 1-year risk of symptomatic ARE vs 3%, 4%, and 8% for no prior treatment, prior whole brain radiotherapy [WBRT], or concurrent WBRT) and any of these volume parameters: target, prescription isodose, 12-Gy, or 10-Gy volume. Excluding lesions treated with repeat SRS, the 1-year probabilities of ARE were < 1%, 1%, 3%, 10%, and 14% for maximum diameter 0.3–0.6 cm, 0.7–1.0 cm, 1.1–1.5 cm, 1.6–2.0 cm, and 2.1–5.1 cm, respectively. The 1-year probabilities of symptomatic ARE leveled off at 13%–14% for brain metastases maximum diameter > 2.1 cm, target volume > 1.2 cm3, prescription isodose volume > 1.8 cm3,12-Gy volume > 3.3 cm3, and 10-Gy volume > 4.3 cm3, excluding lesions treated with repeat SRS. On both univariate and multivariate analysis, capecitabine, but not other systemic therapy within 1 month of SRS, appeared to increase ARE risk. For the multivariate analysis considering only metastases with target volume > 1.0 cm3, risk factors for ARE included prior SRS, kidney primary tumor, connective tissue disorder, and capecitabine.

CONCLUSIONS

Although incidence of ARE after SRS was low overall, risk increased rapidly with size and volume, leveling off at a 1-year cumulative incidence of 13%–14%. This study describes the time course of ARE and provides risk estimates by various lesion characteristics and treatment parameters to aid in decision-making and patient counseling.

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Adib A. Abla, William Caleb Rutledge, Zachary A. Seymour, Diana Guo, Helen Kim, Nalin Gupta, Penny K. Sneed, Igor J. Barani, David Larson, Michael W. McDermott and Michael T. Lawton

OBJECT

The surgical treatment of many large arteriovenous malformations (AVMs) is associated with substantial risks, and many are considered inoperable. Furthermore, AVMs larger than 3 cm in diameter are not usually treated with conventional single-session radiosurgery encompassing the entire AVM volume. Volume-staged stereotactic radiosurgery (VS-SRS) is an option for large AVMs, but it has mixed results. The authors report on a series of patients with high-grade AVMs who underwent multiple VS-SRS sessions with resultant downgrading of the AVMs, followed by resection.

METHODS

A cohort of patients was retrieved from a single-institution AVM patient registry consisting of prospectively collected data. VS-SRS was performed as a planned intentional treatment. Surgery was considered as salvage therapy in select patients.

RESULTS

Sixteen AVMs underwent VS-SRS followed by surgery. Four AVMs presented with rupture. The mean patient age was 25.3 years (range 13–54 years). The average initial Spetzler-Martin grade before any treatment was 4, while the average supplemented Spetzler-Martin grade (Spetzler-Martin plus Lawton-Young) was 7.1. The average AVM size in maximum dimension was 5.9 cm (range 3.3–10 cm). All AVMs were supratentorial in location and all except one were in eloquent areas of the brain, with 7 involving primary motor cortex. The mean number of VS-SRS sessions was 2.7 (range 2–5 sessions). The mean interval between first VS-SRS session and resection was 5.7 years. There were 4 hemorrhages that occurred after VS-SRS. The average Spetzler-Martin grade was reduced to 2.5 (downgrade, −1.5) and the average supplemented Spetzler-Martin grade was reduced to 5.6 (downgrade, −1.5). The maximum AVM size was reduced to an average of 3.0 cm (downsize = −2.9 cm). The mean modified Rankin Scale (mRS) scores were 1.2, 2.3, and 2.2 before VS-SRS, before surgery, and at last follow-up, respectively (mean follow-up, 6.9 years). Fifteen AVMs were cured after surgery. Ten patients had good outcomes at last follow-up (7 with mRS Score 0 or 1, and 3 with mRS Score 2). There were 2 deaths (both mRS Score 1 before treatment) and 4 patients with mRS Score 3 outcome (from mRS Scores 0, 1, and 2 [n = 2]).

CONCLUSIONS

Volume-staged SRS can downgrade AVMs, transforming high-grade AVMs (initially considered inoperable) into operable AVMs with acceptable surgical risks. This treatment paradigm offers an alternative to conservative observation for young patients with unruptured AVMs and long life expectancy, where the risk of hemorrhage is substantial. Difficult AVMs were cured in 15 patients. Surgical morbidity associated with downgraded AVMs is reduced to that of postradiosurgical/preoperative supplemented Spetzler-Martin grades, not their initial AVM grades.

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Hideyuki Kano, Jason Sheehan, Penny K. Sneed, Heyoung L. McBride, Byron Young, Christopher Duma, David Mathieu, Zachary Seymour, Michael W. McDermott, Douglas Kondziolka, Aditya Iyer and L. Dade Lunsford

OBJECT

Stereotactic radiosurgery (SRS) is a potentially important option for patients with skull base chondrosarcomas. The object of this study was to analyze the outcomes of SRS for chondrosarcoma patients who underwent this treatment as a part of multimodality management.

METHODS

Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 46 patients who underwent SRS for skull base chondrosarcomas. Thirty-six patients had previously undergone tumor resections and 5 had been treated with fractionated radiation therapy (RT). The median tumor volume was 8.0 cm3 (range 0.9–28.2 cm3), and the median margin dose was 15 Gy (range 10.5–20 Gy). Kaplan-Meier analysis was used to calculate progression-free and overall survival rates.

RESULTS

At a median follow-up of 75 months after SRS, 8 patients were dead. The actuarial overall survival after SRS was 89% at 3 years, 86% at 5 years, and 76% at 10 years. Local tumor progression occurred in 10 patients. The rate of progression-free survival (PFS) after SRS was 88% at 3 years, 85% at 5 years, and 70% at 10 years. Prior RT was significantly associated with shorter PFS. Eight patients required salvage resection, and 3 patients (7%) developed adverse radiation effects. Cranial nerve deficits improved in 22 (56%) of the 39 patients who deficits before SRS. Clinical improvement after SRS was noted in patients with abducens nerve paralysis (61%), oculomotor nerve paralysis (50%), lower cranial nerve dysfunction (50%), optic neuropathy (43%), facial neuropathy (38%), trochlear nerve paralysis (33%), trigeminal neuropathy (12%), and hearing loss (10%).

CONCLUSIONS

Stereotactic radiosurgery for skull base chondrosarcomas is an important adjuvant option for the treatment of these rare tumors, as part of a team approach that includes initial surgical removal of symptomatic larger tumors.

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Zachary A. Seymour, Penny K. Sneed, Nalin Gupta, Michael T. Lawton, Annette M. Molinaro, William Young, Christopher F. Dowd, Van V. Halbach, Randall T. Higashida and Michael W. McDermott

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.