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Stereotactic Radiosurgery for Intracranial Noncavernous Sinus Benign Meningioma: International Stereotactic Radiosurgery Society Systematic Review, Meta-Analysis and Practice Guideline

Abstract BACKGROUND Stereotactic radiosurgery (SRS) for benign intracranial meningiomas is an established treatment. OBJECTIVE To summarize the literature and provide evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS Articles in English specific to SRS for benign intracranial meningioma, published from January 1964 to April 2018, were systematically reviewed. Three electronic databases, PubMed, EMBASE, and the Cochrane Central Register, were searched. RESULTS Out of the 2844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but one were retrospective studies. The 10-yr local control (LC) rate ranged from 71% to 100%. The 10-yr progression-free-survival rate ranged from 55% to 97%. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. CONCLUSION The current literature supporting SRS for benign intracranial meningioma lacks level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based treatment option (recommendation level II) for grade 1 meningioma.

mostly benign (WHO grade I) lesions, and atypical (WHO grade II) and malignant meningiomas (WHO grade III) are regarded as more aggressive variants. 1 This investigation focuses on WHO grade I meningiomas.
Despite their benign nature, the treatment of meningiomas can be challenging. Gross total resection (GTR) has traditionally represented the treatment of choice and it is potentially curative, although the complete removal of the lesion may be difficult when the tumor is close to and/or invades neural or vascular structures. In these situations, a subtotal removal is generally performed, albeit with lower longterm local control (LC) outcomes. 2,3 Based on the anatomic location, in particular the skull base, surgery may imply significant risks to the patient and cause serious harm. 2,4 For these surgically difficult cases, the treatment strategy has evolved to incorporate some form of radiation, not only as adjuvant or salvage therapy, but as the primary treatment often without tissue confirmation. [5][6][7] Radiation can be delivered with stereotactic precision as a single treatment using a stereotactic radiosurgery (SRS) technique, or as fully fractionated stereotactic radiotherapy (SRT) which is again based on stereotactic principles but typically delivered over 5 to 6 wk and a dose per fraction ranging from 1.8 to 3.0 Gy. With the advent of frameless image-guided SRS systems, there is the ability to deliver SRS in more than one fraction, which is known as hypofractionated stereotactic radiotherapy (HSRT), and typically HSRT refers to no more than 5 fractions and a dose per fraction ≥5 Gy.
On behalf of the International Stereotactic Radiosurgery Society (ISRS) Guideline Committee, this report summarizes the current literature specific to SRS outcomes for WHO Grade I intracranial meningioma, and to provide therapeutic guidelines. Cavernous sinus (CS) meningiomas have been excluded from this analysis as they were the subject of a previous ISRS guideline. 8

Article Selection
The ISRS clinical practice guideline taskforce conducted a systematic review of the literature specific to the management of intracranial meningioma with SRS, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (2009) and the Cochrane guidelines for systematic reviews of interventions. 9 Articles were included when inclusion criteria were met.

Inclusion Criteria
Retrospective and prospective studies reporting outcomes on adult patients with a radiological and/or pathological diagnosis of intracranial WHO grade I meningioma were included. In those series that included other grades of meningioma (WHO grade II and III), only those studies that segregated outcomes for the WHO grade I population were included. Similarly, those studies including CS meningioma were excluded, unless outcomes were segregated for non-CS meningioma. For series reporting outcomes without segregating the study population to non-CS patients and CS patients, an exception was made, provided that the proportion of CS patients included did not exceed 30% to 40% of the overall population. A minimum follow-up period of 3 yr was deemed mandatory for the analysis of LC and progression-free-survival (PFS); series with a mean/median follow-up period lower than 36 mo have been considered if specified the number of patients for which a longer than 3 yr follow-up is available.
Studies which included re-irradiated patients, or whose population amounted to less than 10 patients, were also excluded. SRS and HSRT, delivered over 2 to 5 fractions, were permitted. Lastly, patients who had been treated with primary or adjuvant/salvage SRS were included.

Objectives
The primary objective of the study was to define the efficacy of SRS in the treatment of intracranial WHO grade I meningioma (excluding CS lesions). The primary outcomes analyzed were rates of LC, PFS, and overall survival.
Secondary objectives included analyses of symptoms-control, radiation-induced toxicity, and prognostic factors.

Search Strategy
The Medline, Embase, and Cochrane database were searched for English abstracts and keywords of relevant studies published until June 6, 2018. The details of the search strategy are listed in Table, Supplemental Digital Content 1.
Exclusion criteria have been recorded and listed in Figure 1.

Data Extraction
The extracted data include information on study design, follow-up interval, patient's demographic features, tumor characteristics, treatment parameters (including primary adjuvant and salvage setting), outcomes, and prognostic factors.

Risk-of-Bias Assessment
There is no single recommended instrument to assess the risk of bias for systematic reviews that includes both prospective and retrospective observational studies. We chose to evaluate the risk of bias by using a previously published system based on a 10-item assessment (see Table, Supplemental Digital Content 2). 7 The system was developed to evaluate the kind of bias and the completeness of information. Particularly, items 1 and 2 assess the selection bias, items 3 to 5 the reporting bias, item 6 the attrition bias, and items 7 to 10 assess the extensiveness of information on treatments and outcomes. Specifically, an affirmative answer, "yes," indicates a low risk of bias, while a negative answer, "no," a high risk. Unclear or unknown risks are indicated by the definition "unclear."

Ranking the Evidence Quality
The evidence quality was ranked by applying an evidence hierarchy developed by the ISRS Guidelines Committee for a number of studies: diagnostic, prognostic, therapeutic, and decision modeling. The method used to assess the quality of the evidence is exemplified in this link: https://www.cns.org/guidelines/guideline-development-methodology.

Strength of Recommendation Rating Scheme
Recommendation level I: high degree of clinical certainty (class I evidence or overwhelming class II evidence). Recommendation level II: clinical certainty (class II evidence or a strong consensus of class III evidence).
Recommendation level III: clinical uncertainty (inconclusive or conflicting evidence or opinion).

Statistical Methods
The 3-yr, 5-yr, and 10-yr rates and the respective CI and/or standard errors (SE) for efficacy end points were extracted and reported from each study, where available or deducible.
The percentage of patients with symptom control and the percentage of patients suffering at least from one toxicity (together with the 95% CI) were also extracted or calculated. The Freemen-Tukey double arcsine transformation was performed to obtain the overall estimates, and the DerSimonian-Laird random effect model has been applied to calculate the weighted pooled estimate. The overall estimate was backtransformed.
The STATA software, version 14.3 (StataCorp), has been used to analyze the data.

Selection of the Studies
The PubMed, Embase, and Cochran searches identified 2844 studies. After the removal of duplicates, 2233 papers remained, out of which 1927 were excluded upon title and abstract evaluation. Following a full text scrutiny of the remaining 305 studies, 27 studies 10-36 were deemed to have met the inclusion criteria and selected for this review and summarized in Figure 1. One study was prospective, 19 in 4 studies the study design was unclear, 10,21,24,32 and the remaining studies were retrospective.  Two studies were multicenter, 19,35 while the remaining were single-center institutional series.

Risk-of-Bias Assessment
Based on the established risk-of-bias assessment method, none of the analyzed studies fulfill the criteria for low risk of bias, according to the defined 4 sections (selection bias, reporting bias, attrition bias, extensiveness of information on intervention analyzed). Four studies could be considered at low risk for selection bias, as they enrolled patients in a consecutive manner and reported the reasons to exclude some patients from the study. 19,24,25,28 Five studies were considered at low risk for reporting bias. 15,30,31,33,36 A total of 14 studies should be considered at low risk of attrition bias. 10,11,[13][14][15]17,[19][20][21][23][24][25]27,28 All but one 35 of the series included was at risk of bias with respect to the reporting of the results. Details about the Risk-of-Bias evaluation are reported in Table, Supplemental Digital Content 3.

Patient and Tumor Characteristics
From the reviewed literature summarized in Table 1, a total of 3654 patients (3750 tumors) were included. The median followup was 60 mo. The mean patient age at the time of treatment ranged from 40 to 71 (median, 57 yr). The percentage of male patients across studies ranged from 11% to 41% (median, 26%). The analysis includes WHO grade I meningiomas treated with SRS and HSRT; the grade was based on pathological confirmation or based on radiological assessment. A single study included grade II and II meningiomas; however, WHO grade I tumors were reported separately and, as a result, they have been than included in this analysis. 19 The tumor site distribution is represented in Table 2. The overall tumor volume ranged from 0.5 to 26 cc (median, 6.4 cc), and ranged from 0.5 to 15.2 cc (median, 5.6 cc) in the SRS series and from 7.6 to 26 cc (median, 16.2 cc) in the HSRT series.
Tumor-control rates and the PFS are summarized in Table 3.
The most common schedule for HSRT was 25 Gy in 5 fractions. 16,29,31 The observed HSRT schedules ranged from 14 to 30 Gy delivered in 2 to 5 fractions. The prescription isodose line ranged from 44% to the 95% isodose line.

Primary, Adjuvant, or Salvage Therapy
Approximately half of the study population in this analysis underwent SRS as primary treatment. Two studies found that  previous surgery was associated with worse tumor LC. 21,22 Similarly, El-Khatib et al 18 reported better PFS at 5, 10, and 15 yr when SRS was performed as a primary treatment as opposed to an adjuvant or salvage indication. From the Mayo clinic, Pollock et al 33 also reported prior surgery (hazard ratio: 6.9, P = .002) to be a negative risk factor in terms of local tumor control, as did Sheehan et al, 35 who concluded that more than one prior surgery significantly increased the likelihood of tumor progression after SRS. However, a recent series by Kim et al 25 failed to detect any relationship with prior surgery and LC following SRS.

Imaging and Contouring Techniques
The oldest series included treatments based on computed tomography (CT) images. In more modern series, the target and the critical structures are additionally defined using magnetic resonance imaging (MRI) scans. Specific to the MRI protocol, the T1 axial contrast-enhanced MRI was the most used sequence to define the target volume (TV). The TV was contoured according to the contrast enhancement without any further margin in most of the series. A T2 fast spin echo with a slice thickness of 1 to 1.5 mm could be recommended for inner-ear and/or cranial nerve definition. Two studies specifically debated the inclusion of the dural tail and concluded that it should be included in the TV, although without any specific analysis to support such practice. 11,17
Possible prognostic factors for a negative clinical outcome were higher marginal dose 22 and larger volumes. 33 Two studies 20,33 suggest that the postradiosurgery edema rate may be related to the parafalcine, parasagittal, and convexity locations, while 2 studies 28,30 failed to observe a correlation between tumor location and clinical or radiological toxicity.
The clinical and toxicity data are summarized in Tables 4  and 5.

DISCUSSION
The results of this systematic review support the effectiveness of SRS with respect to LC for WHO grade I meningioma. The 5-yr PFS ranged from 85% to 100% (median, 89%) and the 10-yr PFS ranged from 53% to 100% (median, 85%). These data are consistent with what we observe in the surgical literature 37 and may further explain the reason why SRS is being increasingly used as the primary therapeutic modality for meningioma.
Regarding the dose, the most recent data show that a marginal dose ranging from 15 to 12 Gy is generally sufficient with respect to durable LC. 27,38 With regards to HSRT, the literature lacks the mature longterm outcomes to draw any firm conclusions; however, the preliminary data summarized in this review suggest a potential role of such a technique in selected cases, and the most common fractionation schedule is 25 Gy in 5 fractions.
Whether SRS as a primary treatment is preferable to adjuvant SRS remains to be confirmed. However, the evidence suggests that previous surgery may adversely affect tumor control. 18,21,22,33,35 This could be related to a more complex definition of the target volume due to the complexity of the postoperative radiological images and/or to a potentially more aggressive inherent biology, given that patients required surgery as upfront treatment without a GTR possible. There is no evidence that adjuvant SRS may yield better results than salvage SRS, or vice versa. The choice has been largely been based on the clinician's or institution's preference and by taking into account a variety of factors such as tumor volume and location, previous surgery, clinical condition, age, etc. The specifics with respect to decision making were not stipulated in the relevant series and are beyond the scope of this review.
The issue regarding optimal imaging has not been defined yet; it is very important to establish a common strategy to delineate the TV and critical structures. Most studies define the TV as the contrast-enhanced tumor without margins. The role of biological imaging (CT/MRI positron emission tomography) requires a more in-depth investigation as well. Finally, regarding clinical outcome and toxicity, it is well known that specific treatment-related risks are often closely linked to the tumor location. For example, skull base meningioma often involves cranial nerves, and sparing them becomes challenging both in terms of surgery and SRS. Parasagittal meningiomas are also associated with an increased risk of post-SRS edema, and there is a lack of outcome data co-relating the risk of edema with dose fractionation and volume. The results on neurological toxicity from this review suggest a low risk of neurological deterioration (median 7.4%) and a low rate of serious adverse events (median 8.0%).
The role of the tumor location in term of both tumor control and clinical outcome is also of importance and requires further investigation.
Cognitive status and quality-of-life were not analyzed in the literature reviewed and are an active area of investigation. A summary of recommendations based on this review of the evidence as endorsed by the ISRS are provided in Table 6.
Key Areas for Future Investigation -Although SRS in the treatment of intracranial benign meningioma is being increasingly used, the literature lacks class I and II evidence. Higher-level evidence is needed, particularly in regards to comparative analysis of SRS, HSRT, intensity modulated radiation therapy, charged particle radiation, and the various surgical techniques, in order to help clinicians make optimal therapeutic decisions. -The timing of SRS (primary, adjuvant, or as salvage treatment) requires further investigation.

Recommendations level
Recommendation level II. SRS may be proposed as a primary treatment modality for an asymptomatic or mildly symptomatic meningioma, and should be considered when a complete surgical excision cannot be achieved or is not amenable Recommendation level II. After surgery, when a residual tumor is not evident or is minimal, a wait-and-scan approach appears to be reasonable with a regular radiological follow-up. At the time of recurrence or progression, SRS should be taken into consideration as a treatment modality. Some studies suggest that the recurrence/progression rate is lower when SRS is delivered as the primary treatment as compared to an adjuvant treatment and this remains to be confirmed. Recommendation level III. Single-fraction SRS with a dose of 12 to 15 Gy appears to be sufficient to manage benign intracranial meningioma. A prescription dose of at least 14 Gy would be advisable. Recommendation level III. HSRT may be considered for the treatment of large or/and critically located meningioma. Optimal practice has yet to be defined; however, 25 Gy in 5 fractions is a common approach. Recommendation level III. SRS generally entails a low risk of neurological deterioration. Patients may experience a clinical improvement without tumor shrinkage.
-Before HSRT can be recommended as a standard of care, mature follow-up of existing series is needed and ideally comparative clinical trials, especially for large or meningioma located in critical locations where SRS is limited by dose tolerances. -Further research as to the ideal MR sequence to define the TV, including the dural tail, and the incorporation of multimodal imaging, including biological imaging, is needed. -While there is consensus on the prescription dose for SRS, the best treatment schedule, dose-per-fraction, and total dose for HSRT require further investigations.

Study Limitations
The main limitations with respect to the conclusions from this systematic review lie in the lack of strong evidence and, in general, the lack of a common terminology with respect to endpoints, as pointed out by the risk-of-bias assessment.
The limited number of studies reporting the CI and/or the number of patients at risk at any given time limited the possibility of a meta-analysis about the efficacy.
Randomized controlled trials would be recommended; on the other hand, such studies are unlikely to be performed given current practice patterns, funding constraints, and clinical equipoise.

CONCLUSION
SRS has traditionally been considered to be an adjuvant treatment modality in case of remnants or recurrent tumors, or as primary treatment for patients who are not surgically amenable. Regardless of the indication, SRS represents an important treatment option for most benign intracranial meningiomas.
Given the strong consensus of class III evidence studies with favorable outcomes, today SRS can be considered a primary treatment in many cases (recommendation level II). Tumor control rates are generally high, with rare events of post-SRS deterioration. However, due to the lack of class level I and II evidence, further investigation with longer periods of observation and larger, multiinstitutional series are needed. Finally, the development of common terminology criteria and reporting methodology is desirable to ensure consistency in the interpretation of the evidence.

Disclosures
This evidence-based clinical practice guideline was supported by the International Stereotactic Radiosurgery Society. Dr Sahgal is an advisor/consultant with Elekta (Gamma Knife Icon); belongs to the Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases, and Linac Based SRS Consortia; had past educational seminars with Elekta AB, Accuray Inc, Varian (CNS Teaching Faculty), and BrainLAB; and had a Medtronic Kyphon Research grant with Elekta AB Travel accommodations/expenses by Elekta, Varian, and BrainLAB. Dr Marchetti and Dr Fariselli have grants from Accuray Europe for unrelated research. Mr Paddick is a consultant for and has received a research grant from Elekta AB. Dr Regis is a consultant for and has received research grants from Medtronic and Elekta AB. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Sahgal is an advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), BrainLAB, and VieCure (Medical Advisory Board). Dr Suh is consultant for Abbvie.

Disclaimer
These consensus reviews should not be considered inclusive of all methods of care or exclusive of other methods or care reasonably directed to obtain similar results. The physician must make the ultimate judgment depending on characteristics and circumstances of individual patients. Adherence to this guideline will not ensure successful treatment in every situation. The authors of this guideline and the International Stereotactic Radiosurgery Society assume no liability for the information, conclusions, and recommendations contained in this report.