Journal of Clinical Neuroscience xxx (2014) xxxxxx

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Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Clinical Study

Stereotactic radiosurgery of meningiomas following resection:

Predictors of progression
Colin J. Przybylowski a, Daniel M.S. Raper a, Robert M. Starke a, Zhiyuan Xu a, Kenneth C. Liu a,
Jason P. Sheehan a,b,
a
b

Department of Neurosurgery, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA 22903, USA
Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA, USA

a r t i c l e

i n f o

Article history:
Received 21 July 2014
Accepted 28 July 2014
Available online xxxx
Keywords:
Gamma Knife
Meningioma
Progression
Simpson grade
Stereotactic radiosurgery
WHO grade

a b s t r a c t
Residual or recurrent meningiomas after initial surgical resection are commonly treated with stereotactic
radiosurgery (SRS), but progression of these tumors following radiosurgery is difcult to predict. We performed a retrospective review of 60 consecutive patients who underwent resection and subsequent
Gamma Knife (Elekta AB, Stockholm, Sweden) radiosurgery for residual or recurrent meningiomas at
our institution from 20012012. Patients were subdivided by Simpson resection grade and World Health
Organization (WHO) grade. Cox multivariate regression and KaplanMeier analyses were performed to
assess risk of tumor progression. There were 45 men (75%) and 15 women (25%) with a median age
of 56.8 years (range 26.582 years). The median follow-up period was 34.9 months (range
6108.4 months). Simpson grade 13 resection was achieved in 17 patients (28.3%) and grade 4 resection
in 43 patients (71.7%). Thirty-four tumors (56.7%) were WHO grade 1, and 22 (36.7%) were WHO grade
23. Time from resection to SRS was signicantly shorter in patients with Simpson grade 4 resection
compared to grade 13 resection (p < 0.01), but did not differ by WHO grade (p = 0.17). Post-SRS complications occurred in ve patients (8.3%). Overall, 19 patients (31.7%) experienced progression at a median
of 15.3 months (range 1.261.4 months). Maximum tumor diameter >2.5 cm at the time of SRS (p = 0.02)
and increasing WHO grade (p < 0.01) were predictive of progression in multivariate analysis. Simpson
resection grade did not affect progression-free survival (p = 0.90). The mortality rate over the study period was 8.3%. SRS offers effective tumor control for residual or recurrent meningiomas following resection, especially for small benign tumors.
2014 Elsevier Ltd. All rights reserved.

1. Introduction
Complete or near-complete resection of meningiomas is often
not possible, and even when gross total resection (GTR) is
achieved, tumors may still recur. Recurrence of intracranial meningiomas after resection approaches 20% with long-term follow-up
[1]. Stereotactic radiosurgery (SRS) has gained favor as a minimally
invasive approach to treat residual or recurrent meningiomas after
initial surgical resection. While the combination of microsurgery
and SRS has proven efcacious for tumor control [25], few series
have analyzed for factors predictive of progression following SRS.
Identifying factors associated with future progression is important
for optimal long-term management of these patients and also may
guide neurosurgeons to achieve specic goals during resection.

Corresponding author. Tel.: +1 434 924 8129; fax: +1 434 243 6726.
E-mail address: jsheehan@virginia.edu (J.P. Sheehan).

In order to evaluate the efcacy of SRS to treat residual or recurrent meningiomas, we analyzed rates and predictors of tumor progression in patients who underwent SRS after initial surgical
resection. Evaluations were made between patients with Simpson
grade 13 versus grade 4 resection and between World Health
Organization (WHO) grade 1 versus grade 23 tumors.
2. Patients and methods
2.1. Patient population
We performed a retrospective review of an Institutional Review
Board approved database containing 518 consecutive patients
treated with Gamma Knife radiosurgery (Elekta AB, Stockholm,
Sweden) for intracranial meningiomas at the University of Virginia
from 20012012. Patients were excluded from analysis if they did
not undergo previous resection at our institution or had less than
6 months of follow-up data.

http://dx.doi.org/10.1016/j.jocn.2014.07.028
0967-5868/ 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Przybylowski CJ et al. Stereotactic radiosurgery of meningiomas following resection: Predictors of progression. J Clin
Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.07.028

C.J. Przybylowski et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

2.2. Operative classication

Resection grade was classied according to the Simpson grading
system through retrospective review of operative notes by a neurosurgeon blinded to outcome as follows: grade 1 = GTR including
resection of underlying bone and associated dura; grade 2 = GTR
including coagulation of dural attachment; grade 3 = GTR without
removal or coagulation of dural attachment; and grade 4 = subtotal
resection [6]. The 2007 WHO criteria were utilized for histopathologic diagnosis for patients who underwent surgery since 2007
[7]. The 2000 WHO criteria was utilized for patients who underwent surgery from 20012006 [8]. Skull base location included
the following tumor sites: olfactory groove, planum sphenoidale,
cerebellopontine (CP) angle, Meckels cave, clinoidal, petroclival,
suprasellar, and cavernous sinus.
2.3. SRS
Our radiosurgical technique has been previously described
[9,10]. Patients underwent placement of a Leksell model G stereotactic frame (Elekta Instruments, Norcross, GA, USA) in the operating room under monitored anesthetic care. Pre- and post-contrast
thin-slice (1 mm) volume acquisition axial and coronal MRI
sequences were then obtained for treatment planning. Thin-slice
stereotactic CT scan was obtained with and without contrast for
patients with medical contraindications to MRI. Radiosurgical dose
plans were constructed by a neurosurgeon, medical physicist and
radiation oncologist. Elektas Gamma Plan software was used for
dose planning. Since 2007, we have used the Gamma Knife Perfexion system. Prior to that, we used the Leksell Gamma Unit Model U
until July 2001 when the C Model (Elekta Instruments) replaced it.
All patients in this series were treated with single session
radiosurgery.
2.4. Clinical and radiological follow-up
Patients were routinely followed with clinical and radiological
follow-up every 6 months for WHO grade 1 meningiomas and
every 3 months for WHO grade 23 meningiomas. Follow-up was
performed preferentially at the University of Virginia. If patients
were unable to travel to our institution, follow-up imaging and
neurologic status were obtained in correspondence with outside
referring hospitals and patients local primary care physicians. All
imaging studies were reviewed by a University of Virginia neurosurgeon and neuroradiologist. Radiological progression was
dened as a P15% increase in tumor volume as compared to the
volume at the time of SRS [11]. Overall progression was dened
as patients with neurological deterioration in relation to their
tumors or tumors with radiological progression requiring further
treatment, including surgical resection, SRS or chemotherapy.
Peritumoral edema was dened as the presence of post-SRS
T2-weighted hyperintensity changes around the tumor. Clinical
correlation in patients experiencing headaches, seizures and/or
focal neurological decits established symptomatic peritumoral
edema.
2.5. Statistical analysis
Statistical analyses of categorical variables were carried out
using chi-squared and Fishers exact tests. Statistics of means were
carried out using unpaired Students t-test and Wilcoxon rank sum
tests when variables were not normally distributed. KaplanMeier
analysis was performed for risk of tumor progression. Factors predictive of tumor progression (p < 0.15) [12] were entered into Cox
regression analysis to assess hazard ratios. The covariates analyzed
included sex, tumor location, proliferative index, history of previ-

ous resection, history of previous radiotherapy, tumor diameter,

Simpson grade, WHO grade, SRS margin dose and number of isocenters. Clinically signicant variables and interaction expansion
covariates were further assessed in both Cox and logistic multivariable analysis as deemed relevant. p-values of 60.05 were considered statistically signicant.
3. Results
3.1. Patient and tumor characteristics
We identied 60 patients who underwent surgical resection at
our institution and subsequently received SRS for residual or recurrent meningiomas. Preoperative patient and tumor characteristics
are summarized in Table 1. There were 45 women (75%) and 15
men (25%) with a median age of 56.8 years (range 26.582 years)
at the time of resection. Prior to surgical resection at our institution, 18 patients (30%) had undergone previous resection and 10
patients (16.7%) had undergone previous radiotherapy. Of these
10 patients with previous radiotherapy, eight had been previously
diagnosed with WHO grade 2 tumors and two had been previously
diagnosed with WHO grade 3 tumors. The most common tumor
locations were parasagittal (n = 13; 21.7%) and CP angle (n = 9;
15.0%). The median maximum tumor diameter prior to resection
was 4.2 cm (range 1.37.9 cm).
Operative ndings are summarized in Table 2. Simpson grade
13 resection was achieved in 17 patients (28.3%) and grade 4
resection in 43 patients (71.7%). Thirty-four tumors (56.7%) were
Table 1
Preoperative patient and tumor characteristics
Characteristic
Female
Age at surgery, yearsa
Previous resection
Previous radiotherapy
Location
Parasagittal
CP angle
Suprasellar
Sphenoid wing
Convexity
Petroclival
Clinoid
Planum sphenoidale
Olfactory groove
Posterior fossa
Middle cranial fossa
Cavernous sinus
Maximum diameter, cma

Number (%)
45 (75.0)
56.8 (26.582)
18 (30.0)
10 (16.7)
13 (21.7)
9 (15.0)
6 (10.0)
6 (10.0)
6 (10.0)
4 (6.7)
4 (6.7)
4 (6.7)
4 (6.7)
2 (3.3)
1 (1.7)
1 (1.7)
4.2 (1.37.9)

CP = cerebellopontine.
a
Median (range).

Table 2
Operative ndings
Characteristic

Number (%)

Simpson grade
Grade 1
Grade 2
Grade 3
Grade 4

1
12
4
43

(1.7)
(20.0)
(6.7)
(71.7)

WHO grade
Grade 1
Grade 2
Grade 3
Unknown

34
19
3
4

(56.7)
(31.7)
(5.0)
(6.7)

WHO = World Health Organization.

Please cite this article in press as: Przybylowski CJ et al. Stereotactic radiosurgery of meningiomas following resection: Predictors of progression. J Clin
Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.07.028

C.J. Przybylowski et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

Table 3
Stereotactic radiosurgery treatment characteristics and complications

Patients, number
Age at SRS, years
Maximum tumor size treated by SRS, cm
Time between resection and SRS, months
Margin dose, Gy
Maximum dose, Gy
Number of isocenters
Complications
None
Peritumoral edema headache
Increased seizure frequency
Transient facial paresthesia

Total

Simpson grade 13

Simpson grade 4

WHO grade 1

WHO grade 23

60
58.7 (3083)
3.0 (0.75.1)
7.9 (1.385.4)

17
59.7 (3875)
3.0 (2.04.4)
22.2 (3.585.4)

43
57.4 (3083)
2.9 (0.75.1)
6.2*(1.366.7)

34
57.7 (3183)
3.0 (0.74.8)
5.6 (1.385.4)

22
61.1 (3083)
3.0 (1.45.1)
8.9 (1.371.4)

15 (623)
30 (1246)
17 (631)

15 (623)
30 (1246)
18 (1227)

14 (620)
30 (1240)
16 (631)

14 (615)
28 (1240)
17 (631)

16 (623)
32 (1246)
17 (927)

15 (88.2)
1 (5.9)
1 (5.9)
0

40 (93.0)
2 (4.7)
0
1 (2.3)

55
3
1
1

(91.7)
(5.0)
(1.7)
(1.7)

31
1
1
1

(91.2)
(2.9)
(2.9)
(2.9)

20 (90.9)
2 (9.1)
0
0

Values are presented as median (range) or number (%).

SRS = stereotactic radiosurgery, WHO = World Health Organization.
*
Statistically signicant difference, p 6 0.05.

diagnosed histologically as WHO grade 1 and 22 (36.7%) as WHO

grade 23. WHO grade was not documented in four tumors (6.7%).
3.2. SRS and complications
SRS treatment characteristics and post-SRS complications are
detailed in Table 3. The median maximum diameter was 3 cm
(range 0.75.1 cm) at the time of SRS. The overall median margin
and maximum doses were 15 Gy (range 623 Gy) and 30 Gy (range
1246 Gy), respectively. Five patients (8.3%) experienced post-SRS
complications. Three patients (5.0%) experienced headaches due
to post-SRS peritumoral edema. All three patients symptoms
responded to a single trial of steroids. One patient (1.7%) with symptomatic localization-related epilepsy experienced temporary worsening of seizure frequency following treatment. Seizure frequency
returned to baseline in 3 months after adjustment of anticonvulsant
medications. One patient (1.7%) with a CP angle meningioma experienced transient facial paresthesias following SRS. This responded
to anticonvulsant medication, but the patient had continuing mild
facial numbness in the left trigeminal nerve distribution at last follow-up. All ve patients who experienced post-SRS complications
had tumors with a maximum diameter larger than 2.8 cm. There
were no signicant differences in SRS parameters or post-SRS complication rates between patients with Simpson grade 13 versus
grade 4 resection or between patients with WHO grade 1 versus
grade 23 tumors. Patients with Simpson grade 4 resection had a
signicantly shorter time from surgical resection to SRS than those
with Simpson grade 13 resection (p < 0.01).
3.3. Progression and further treatment
Progression rates and further treatment after SRS are detailed in
Table 4. Overall, 19 patients (31.7%) experienced progression at a

median of 15.3 months (range 1.261.4 months). The most common further treatment modality was resection, which occurred
in 11 of 19 (57.9%) patients with progression. Resection alone
was performed in eight patients (13.3%); resection with chemotherapy in two patients (3.3%); and resection plus SRS in one
patient (1.7%). SRS alone was performed for progression in four
patients (6.7%), and chemotherapy alone was given in four patients
(6.7%). The median follow-up period was 34.9 months (range
6108.4 months). There were ve deaths (8.3%) over the study
period. Two (3.3%) of these deaths were related to intracranial
progression. Both patients had a history of a WHO grade 2 meningioma. Specimens from the subsequent surgical resection performed at our institution to treat progression showed both
tumors had converted to malignant WHO grade 3.
Median time to progression, median time to retreatment, median follow-up time and mortality rates did not differ between
patients with Simpson grade 13 and grade 4 resection or between
patients with WHO grade 1 and grade 23 tumors. There was no
difference in progression-free survival (PFS) for patients with
Simpson grade 13 (35.3%) versus grade 4 resection (30.2%)
(p = 0.90). Tumors progressed in ve of 34 patients (14.7%) with
WHO grade 1 meningiomas compared with 14 of 22 patients
(63.6%) with WHO grade 23 meningiomas.
Univariate predictors of progression included location other
than skull base (hazard ratio [HR] 4.5, 95% condence interval
[CI]: 1.613, p < 0.01), higher proliferative index (HR 2.2, 95% CI:
1.43.7, p < 0.01), history of previous resection (HR 2.4, 95% CI:
0.956.1, p = 0.06), history of previous radiotherapy (HR 11, 95%
CI: 3.929, p < 0.01), diameter >2.5 cm at the time of SRS (HR 12,
95% CI: 1.694, p = 0.02), increasing WHO grade (HR 7.3, 95% CI:
3.117, p < 0.01) and increasing margin dose (HR 1.2, 95% CI:
1.01.4, p = 0.03). In multivariate analysis, maximum tumor diameter >2.5 cm at the time of SRS (HR 16, 95% CI: 1.6167, p = 0.02)

Table 4
Progression and outcomes after stereotactic radiosurgery

Patients, number
Progression
Time to progression, months
Time to retreatment, months
Followup, months
Death

Total

Simpson grade 13

Simpson grade 4

WHO grade 1

WHO grade 23

60
19 (31.7)
15.3 (1.261.4)
17.9 (1.263.3)
34.9 (3.5108.4)
5 (8.3)

17
6 (35.3)
14.8 (5.556.8)
18.2 (6.360.1)
44.2 (5.576.8)
0

43
13 (30.2)
15.3 (1.261.4)
17.5 (1.263.3)
32.4 (3.5108.4)
5 (11.6)

34
5 (14.7)
48.9 (1.661.4)
50.2 (2.263.3)
32.4 (3.5100.7)
2 (5.9)

22
14 (63.6)*
11.8 (1.235.1)
15.9 (1.244.6)
33.1 (4.276.5)
3 (13.6)

Values are presented as median (range) or number (%).

SRS = stereotactic radiosurgery, WHO = World Health Organization.
*
Statistically signicant difference, p 6 0.05.

Please cite this article in press as: Przybylowski CJ et al. Stereotactic radiosurgery of meningiomas following resection: Predictors of progression. J Clin
Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.07.028

C.J. Przybylowski et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

Fig. 1. KaplanMeier analysis for progression-free survival comparing patients

with meningiomas greater than and less than 2.5 cm at the time of stereotactic
radiosurgery.

Fig. 2. KaplanMeier analysis for progression-free survival comparing patients

with World Health Organization (WHO) grade 1 and WHO grade 23 meningiomas.

(Fig. 1) and increasing WHO grade (HR 9.8, 95% CI: 3.826, p < 0.01)
(Fig. 2) were predictive of progression.

4. Discussion
Residual or recurrent meningiomas after initial surgical resection are commonly treated with SRS. While the combination of
microsurgical resection and SRS yields high rates of tumor control,
knowledge of factors predictive of tumor progression is useful to
guide post-treatment management of these patients. In our series
of patients undergoing surgical resection and subsequent SRS for
residual or recurrent meningiomas, maximum tumor size
>2.5 cm at the time of SRS (p = 0.02, Fig. 1) and WHO grade 23
(p < 0.01, Fig. 2) were found to be predictors of future progression.

Atypical and malignant meningiomas are known to be at

increased risk of future progression after treatment with SRS
[1319]. In a recent review of 19 SRS series for WHO grade 2 and
3 meningiomas, the median 5 year PFS rates were 59% and 13%,
respectively, although results varied widely among studies [13].
In contrast, long-term tumor control rates of WHO grade 1 meningiomas consistently exceed 85% in large SRS series [20]. Due to the
aggressive nature of atypical and malignant meningiomas, some
suggest adjuvant SRS after complete or near-complete GTR should
be offered for all patients. It is unclear whether this approach
improves long-term outcomes. Komotar et al. [21] retrospectively
compared 45 patients who underwent GTR plus SRS or GTR alone.
Twelve of 13 patients (92%) with GTR plus adjuvant SRS did not
experience progression, compared with 19 of 32 patients (59%)
with GTR alone. Their results showed a strong trend towards a benet for adjuvant SRS, but it did not reach statistical signicance
(p = 0.085). Hardesty et al. [22] reported no difference in the overall PFS of 32 patients who underwent SRS after aggressive microsurgical resection compared to those who did not (p = 0.99). In a
subgroup analysis, even those patients with subtotal resection
did not see a benet from adjuvant SRS compared to those without
adjuvant SRS (p = 0.16). While currently there is no indication for
adjuvant SRS after GTR, the timing of SRS after progression is
observed may be important. Results from two series suggested that
earlier delivery of SRS after identication of tumor remnants
decreased future progression of higher grade meningiomas [23,24].
Postoperative radiation therapy is often given for atypical and
malignant meningiomas. Irradiated tumor cells may acquire
radio-resistance that limits the effectiveness of subsequent SRS.
In our study, previous radiotherapy was a predictor of progression
in univariate analysis (p < 0.01), but not in multivariate analysis.
This is likely because all 10 patients who had undergone prior radiation therapy had atypical or malignant tumors. Our study is too
small to fully delineate whether prior radiation therapy contributes to SRS resistance or is just reective of an inherently more
aggressive tumor.
Larger tumor size prior to SRS is likely to affect the ability of SRS
to achieve long lasting PFS [4]. Thus, neurosurgeons should strive
for the fullest extent of resection possible while still preserving
neurological function. A recent study by Oya et al. [25] demonstrated that meningiomas >2.5 cm were associated with a shorter
time to progression (p = 0.0004) and higher annual growth rate
(p < 0.0001). This is consistent with our ndings. Several other series have found that tumor volume above 8 cm3 (which correlates to
a maximal diameter of approximately 2.5 cm) is predictive of a
worse prognosis following SRS [2629]. SRS of large tumors may
also yield higher post-SRS complication rates [30]. All ve patients
who experienced post-SRS complications in this series had tumors
larger than 2.8 cm.
Simpson resection grade did not affect PFS in our study. Simpson et al. [6] rst described the importance of aggressive bony
and dural resection in 1957. While several series in the following
decades validated this concept [1,3134], these studies were conducted prior to introduction of the advanced tools utilized in current neurosurgical practice, such as high quality MRI guidance
and the operative microscope. In the modern era, the precise correlation between Simpson grade and PFS has been challenged.
Heald et al. [35] reported a signicant difference in 3 year PFS rates
between 183 patients with WHO grade 1 meningiomas after Simpson grade 1 (95%) and grade 4 (67%) resection (p = 0.04). Similarly,
Oya et al. [36] found Simpson grade 4 resection to be associated
with a signicantly shorter recurrence-free survival than Simpson
grade 13 resection (p < 0.01) in 240 patients. However, Sughrue
and colleagues [37] reported no substantial difference in the 5 year
PFS rates of 373 patients receiving a Simpson grade 1, 2, 3 or 4
resection for WHO grade 1 meningiomas. While their preoperative

Please cite this article in press as: Przybylowski CJ et al. Stereotactic radiosurgery of meningiomas following resection: Predictors of progression. J Clin
Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.07.028

C.J. Przybylowski et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

embolization rate was higher than normal, a subgroup analysis of

266 patients who did not undergo preoperative embolization also
showed no signicant difference among Simpson grades.
Because our patients all received postoperative SRS, our results
are not directly comparable to series limited to surgical resection.
Nevertheless, our results argue against putting patients at increased
risk of complication with overly aggressive surgical removal when
SRS is available to treat small tumor remnants. Due to the proven
efcacy of SRS to control small-to-moderately sized meningiomas,
the combination of microsurgery and SRS results in high rates of
tumor control [25]. The goals of surgical resection of meningiomas
should remain to decrease mass effect, decompress critical neurovascular structures, and obtain tissue for diagnosis. In the setting
of subtotal resection or recurrence after GTR, SRS is an effective
treatment modality for tumor control, especially for benign meningiomas less than 2.5 cm. For patients with atypical, malignant or
large (>2.5 cm) residual or recurrent meningiomas, close surveillance with serial imaging is warranted, as these tumors are at higher
risk of progression.
4.1. Study limitations
Our study is limited by its retrospective nature. Since this is a
single institution study, there are also inherent patient selection
and treatment biases. Although our treatment parameters were
very similar among patients with different Simpson resection
grades and WHO grades, there was a signicantly shorter time
from resection to SRS for patients with Simpson grade 4 resection
compared to Simpson grade 13 resection. Our study also did not
differentiate between residual or recurrent tumors, and recurrent
tumors may represent more aggressive lesions, irrespective of
WHO grade. Lastly, grouping meningiomas with different WHO
and Simpson grades for outcome analysis may decrease the specicity of the overall results.
5. Conclusion
SRS offers effective tumor control for residual or recurrent
meningiomas following resection, especially for small benign
tumors. Tumors with a maximum diameter of >2.5 cm at the time
of SRS and WHO grade 23 tumors were associated with a higher
risk of progression.
Conicts of Interest/Disclosures
The authors declare that they have no nancial or other conicts of interest in relation to this research and its publication.
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Please cite this article in press as: Przybylowski CJ et al. Stereotactic radiosurgery of meningiomas following resection: Predictors of progression. J Clin
Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.07.028