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Michael E. Ivan, Michael E. Sughrue, Aaron J. Clark, Ari J. Kane, Derick Aranda, Igor J. Barani and Andrew T. Parsa

Object

Because of the rarity of glomus jugulare tumors, a variety of treatment paradigms are currently used. There is no consensus regarding the optimal management to control tumor burden while minimizing treatment-related morbidity. In this study, the authors assessed data collected from 869 patients with glomus jugulare tumors from the published literature to identify treatment variables that impacted clinical outcomes and tumor control rates.

Methods

A comprehensive search of the English-language literature identified 109 studies that collectively described outcomes for patients with glomus jugulare tumors. Univariate comparisons of demographic information between treatment cohorts were performed to detect differences in the sex distribution, age, and Fisch class of tumors among various treatment modalities. Meta-analyses were performed on calculated rates of recurrence and cranial neuropathy after subtotal resection (STR), gross-total resection (GTR), STR with adjuvant postoperative radiosurgery (STR+SRS), and stereotactic radiosurgery alone (SRS).

Results

The authors identified 869 patients who met their inclusion criteria. In these studies, the length of follow-up ranged from 6 to 256 months. Patients treated with STR were observed for 72 ± 7.9 months and had a tumor control rate of 69% (95% CI 57%–82%). Those who underwent GTR had a follow-up of 88 ± 5.0 months and a tumor control rate of 86% (95% CI 81%–91%). Those treated with STR+SRS were observed for 96 ± 4.4 months and had a tumor control rate of 71% (95% CI 53%–83%). Patients undergoing SRS alone had a follow-up of 71 ± 4.9 months and a tumor control rate of 95% (95% CI 92%–99%). The authors' analysis found that patients undergoing SRS had the lowest rates of recurrence of these 4 cohorts, and therefore, these patients experienced the most favorable rates of tumor control (p < 0.01). Patients who underwent GTR sustained worse rates of cranial nerve (CN) deficits with regard to CNs IX–XI than those who underwent SRS alone; however, the rates of CN XII deficits were comparable.

Conclusions

The authors' analysis is limited by the quality and accuracy of these studies and may reflect source study biases, as it is impossible to control for the quality of the data reported in the literature. Finally, due to the diverse range of data presentation, the authors found that they were limited in their ability to study and control for certain variables. Some of these limitations should be minimized with their use of meta-analysis methods, which statistically evaluate and adjust for between-study heterogeneity. These results provide the impetus to initiate a prospective study, appropriately controlling for variables that can confound the retrospective analyses that largely comprise the existing literature.

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Editorial

Cavernous sinus meningiomas

Atul Goel and Manu Kothari

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Michael E. Sughrue, Martin J. Rutkowski, Derick Aranda, Igor J. Barani, Michael W. McDermott and Andrew T. Parsa

Object

Definitive data allowing clinicians to predict which meningioma patients will fail to respond to conservative management are lacking. To address this need, the authors systematically reviewed the published literature regarding the natural history of small, untreated meningiomas.

Methods

The authors performed a systematic review of the existing literature on untreated meningiomas that were followed with serial MR imaging. They summarize the published linear rates of tumor growth, and the risk factors for development of new or worsened symptoms during follow-up by using a stratified chi-square test.

Results

The search methods identified 22 published studies reporting on 675 patients with untreated meningiomas followed by serial MR imaging. Linear growth rates varied significantly: no growth was the most common rate, although reports of more aggressive tumors noted growth rates of up to a 93% linear increase in size per year. The authors found that few patients with initial tumor diameters < 2 cm went on to develop new or worsened symptoms over a median follow-up period of 4.6 years. Patients with initial tumor diameters of 2–2.5 cm demonstrated a marked difference in the rate of symptom progression if their tumors grew > 10% per year, compared with those tumors growing ≤ 10% per year (42% vs 0%; p < 0.001, chi-square test). Patients with tumors between > 2.5 and 3 cm in initial size went on to develop new or worsened symptoms 17% of the time.

Conclusions

This systematic review of the literature regarding the clinical behavior of untreated meningiomas suggests that most meningiomas ≤ 2.5 cm in diameter do not proceed to cause symptoms in the approximately 5-year period following their discovery. Those that do cause symptoms can usually be predicted with close radiographic follow-up. Based on these findings, the authors suggest the importance of observation in the early course of treatment for small asymptomatic meningiomas, especially those with an initial diameter < 2 cm.

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Michael E. Sughrue, Martin J. Rutkowski, Derick Aranda, Igor J. Barani, Michael W. McDermott and Andrew T. Parsa

Object

Although there is a considerable volume of literature available on the treatment of patients with cavernous sinus meningiomas (CSMs), most of the data regarding tumor control and survival come from case studies or single-institution series. The authors performed a meta-analysis of reported tumor control and survival rates of patients described in the published literature, with an emphasis on specific prognostic factors.

Methods

The authors systematically analyzed the published literature and found more than 3000 patients treated for CSMs. Separate meta-analyses were performed to calculate pooled rates of recurrence and cranial neuropathy after 1) gross-total resection, 2) subtotal resection without adjuvant postoperative radiotherapy or radiosurgery, and 3) stereotactic radiosurgery (SRS) alone. Results were expressed as pooled proportions, and random-effects models were used to incorporate any heterogeneity present to generate a pooled proportion. Individual studies were weighted using the inverse variance method, and 95% CIs for each group were calculated from the pooled proportions.

Results

A total of 2065 nonduplicated patients treated for CSM met inclusion criteria for the analysis. Comparisons of the 95% CIs for recurrence of these 3 cohorts revealed that SRS-treated patients experienced improved rates of recurrence (3.2% [95% CI 1.9–4.5%]) compared with either gross-total resection (11.8% [95% CI 7.4–16.1%]) or subtotal resection alone (11.1% [95% CI 6.6–15.7%]) (p < 0.01). The authors found that the pooled mixed-effects rate of cranial neuropathy was markedly higher in patients undergoing resection (59.6% [95% CI 50.3–67.5%]) than for those undergoing SRS alone (25.7% [95% CI 11.5–38.9%]) (p < 0.05).

Conclusions

Radiosurgery provided improved rates of tumor control compared with surgery alone, regardless of the subjective extent of resection.

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Ari J. Kane, Michael E. Sughrue, Martin J. Rutkowski, Derick Aranda, Steve A. Mills, Raphael Buencamino, Shanna Fang, Igor J. Barani and Andrew T. Parsa

Object

There is no Class I evidence to guide the appropriate management of esthesioneuroblastoma (EN). Most data currently guiding treatment come from small- or modest-sized series gathered at individual centers that have concluded that surgery with radiotherapy is the preferred treatment. In this study, the authors summarize the published literature on treatment outcomes in patients with EN. The objective was to ascertain what variables predict prognosis in these patients and to determine the relative effect of different therapies.

Methods

The authors identified 205 published studies containing treatment outcomes for surgery, radiotherapy, chemotherapy, or multimodal treatment. Using Kaplan-Meier analysis, the survival of patients who received surgery was compared with that in those who received surgery and radiotherapy. Additionally, Kadish staging was compared with low- and high-grade Hyams criteria to assess for subgroup prognostic significance in survival differences.

Results

Nine hundred fifty-six patients met the inclusion criteria, with a median follow-up time of 3 years. Kaplan-Meier analysis demonstrated no difference in survival between patients who underwent surgery alone and those who underwent surgery plus radiotherapy at 5 years (78 vs 75%) or 10 years (67 vs 61%, respectively) (p = 0.3). Univariate analysis demonstrated worse survival in cases involving Kadish Grade C tumors, Hyams Grade 3 and 4 tumors, and in patients older than 65 years of age. Multivariate analysis demonstrated that Hyams Grade 3 and 4 lesions carried significant risk (proportional hazard = 4.83, p < 0.001) with 5- and 10-year survival of 47 and 31%.

Conclusions

A biopsy should always be obtained in cases suspected of EN because histology is a strong prognostic indicator and will help guide appropriate treatment. Unimodal surgery and combined surgery/radiotherapy appear to be of equivalent efficacy with respect to survival in patients with EN. Chemotherapy should be considered in high-grade EN.

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Martin J. Rutkowski, Michael E. Sughrue, Ari J. Kane, Derick Aranda, Steven A. Mills, Igor J. Barani and Andrew T. Parsa

Object

Intracranial hemangiopericytoma (HPC) is a rare and malignant extraaxial tumor with a high proclivity toward recurrence and metastasis. Given this lesion's rarity, little information exists on prognostic factors influencing mortality rates following treatment with surgery or radiation or both. A systematic review of the published literature was performed to ascertain predictors of death following treatment for intracranial HPC.

Methods

The authors identified 563 patients with intracranial HPC in the published literature, 277 of whom had information on the duration of follow-up. Statistical analysis of survival was performed using Kaplan-Meier and Cox regression analysis.

Results

Hemangiopericytoma was diagnosed in 246 males and 204 females, ranging in age from 1 month to 80 years. Among patients treated for HPC, overall median survival was 13 years, with 1-, 5-, 10-, and 20-year survival rates of 95%, 82%, 60%, and 23%, respectively. Gross-total resection alone (105 patients) was associated with superior survival rates overall, with a median survival of 13 years, whereas subtotal resection alone (23 patients) resulted in a median survival of 9.75 years. Subtotal resection plus adjuvant radiotherapy led to a median survival of 6 years. Gross-total resection was associated with a superior survival benefit to patients regardless of the addition or absence of radiation, and patients receiving > 50 Gy of radiation had worse survival outcomes (median survival 4 vs 18.6 years, p < 0.01, log-rank test). Patients with tumors of the posterior fossa had a median survival of 10.75 versus 15.6 years for those with non–posterior fossa tumors (p < 0.05, log-rank test).

Conclusions

Treatment with gross-total resection provides the greatest survival advantage and should be pursued aggressively as an initial therapy. The addition of postoperative adjuvant radiation does not seem to confer a survival benefit.

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Isaac Yang, Michael E. Sughrue, Martin J. Rutkowski, Rajwant Kaur, Michael E. Ivan, Derick Aranda, Igor J. Barani and Andrew T. Parsa

Object

Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas.

Methods

The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis.

Results

There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test).

Conclusions

Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

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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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Leland Rogers, Igor Barani, Marc Chamberlain, Thomas J. Kaley, Michael McDermott, Jeffrey Raizer, David Schiff, Damien C. Weber, Patrick Y. Wen and Michael A. Vogelbaum

Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma.

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Lijun Ma, Paula Petti, Brian Wang, Martina Descovich, Cynthia Chuang, Igor J. Barani, Sandeep Kunwar, Dennis C. Shrieve, Arjun Sahgal and David A. Larson

Object

Technical improvements in commercially available radiosurgery platforms have made it practical to treat a large number of intracranial targets. The goal of this study was to investigate whether the dose to normal brain when planning radiosurgery to multiple targets is apparatus dependent.

Methods

The authors selected a single case involving a patient with 12 metastatic lesions widely distributed throughout the brain as visualized on contrast-enhanced CT. Target volumes and critical normal structures were delineated with Leksell Gamma Knife Perfexion software. The imaging studies including the delineated contours were digitally exported into the CyberKnife and Novalis multileaf collimator–based planning systems for treatment planning using identical target dose goals and dose-volume constraints. Subsets of target combinations (3, 6, 9, or 12 targets) were planned separately to investigate the relationship of number of targets and radiosurgery platform to the dose to normal brain.

Results

Despite similar target dose coverage and dose to normal structures, the dose to normal brain was strongly apparatus dependent. A nonlinear increase in dose to normal brain volumes with increasing number of targets was also noted.

Conclusions

The dose delivered to normal brain is strongly dependent on the radiosurgery platform. How general this conclusion is and whether apparatus-dependent differences are related to differences in hardware design or differences in dose-planning algorithms deserve further investigation.