radiosurgery for large-volume (> 10 cm ) benign meningiomas8 months after srs of a petroclival...

J Neurosurg / Volume 112 / May 2010

J Neurosurg 112:951–956, 2010

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MeningioMas are typically benign and slow-grow-ing tumors that account for 15% of intracranial neoplasms in adults. Although many menin-

giomas are discovered when they are small, larger tumors remain common because the mass effect they exert gen-erally occurs over many years, and the brain is able to compensate and continue to function normally. Manage-ment of larger meningiomas is typically more difficult, especially for tumors located adjacent to the major dural

sinuses and skull base regions.3,4,13,14 Complete resection of meningiomas is the preferred treatment when this can be accomplished safely,18 but subtotal resection followed by fractionated radiotherapy or SRS is often performed when the risk of total removal is prohibitive.6,10,12,16,19

The dose/volume relationship and how it relates to postradiosurgical complications has been well document-ed.5 Nonetheless, the progressive trend to treat benign tumors with lower radiation doses theoretically permits patients with larger lesions to be considered for SRS.7 In this study, we review the radiosurgical experience at our center for patients with benign meningiomas > 10 cm3 in volume.

Radiosurgery for large-volume (> 10 cm3) benign meningiomas

Clinical articleJonathan M. Bledsoe, M.d.,1 Michael J. link, M.d.,1 scott l. stafford, M.d.,2 Paul J. Park, M.d.,1 and Bruce e. Pollock, M.d.1,2

Departments of 1Neurological Surgery and 2Radiation Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota

Object. Stereotactic radiosurgery (SRS) has proven to be a safe and effective treatment for many patients with intracranial meningiomas. Nevertheless, the morbidity associated with radiosurgery of larger meningiomas is poorly understood.

Methods. The authors performed a retrospective review of 116 patients who underwent SRS for meningiomas (WHO Grade I) > 10 cm3 between 1990 and 2007, with a minimum follow-up of 12 months. Patients with atypical or malignant meningiomas and those who received prior radiotherapy were excluded. The average tumor volume was 17.5 cm3 (range 10.1–48.6 cm3); the average tumor margin dose was 15.1 Gy (range 12–18 Gy); and the mean follow-up duration was 70.1 months (range 12–199 months).

Results. Tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. Thirty complications after radiosurgery were noted in 27 patients (23%), including 7 cases of seizures, 6 cases of hemiparesis, 5 cases of trigeminal injury, 4 cases of headaches, 3 cases of diplopia, 2 cases each of cerebral infarction and ataxia, and 1 case of hearing loss. Patients with supratentorial tumors experienced a higher complication rate compared with patients with skull base tumors (44% compared with 18%) (hazard ratio 2.9, 95% CI 1.3–6.7, p = 0.01).

Conclusions. The morbidity associated with SRS for patients with benign meningiomas > 10 cm3 is greater for supratentorial tumors compared with skull base tumors. Whereas radiosurgery is relatively safe for patients with large-volume skull base meningiomas, resection should remain the primary disease management for the majority of patients with large-volume supratentorial meningiomas. (DOI: 10.3171/2009.8.JNS09703)

key Words • complication • meningioma • stereotactic radiosurgery

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Abbreviations used in this paper: GKS = Gamma Knife surgery; HR = hazard ratio; ICA = internal carotid artery; PIV = prescription isodose volume; SRS = stereotactic radiosurgery.

J. M. Bledsoe et al.

952 J Neurosurg / Volume 112 / May 2010

MethodsPatient Population

The institutional review board at the Mayo Clinic College of Medicine in Rochester, Minnesota, approved all aspects of this study. A prospectively maintained com-puter database was used to identify 562 patients with 679 intracranial meningiomas who had undergone radiosur-gery at our institution between 1990 and 2007. Patients with tumors < 10 cm3 (470 lesions), atypical meningiomas (20), malignant meningiomas (17), prior radiation therapy (21), neurofibromatosis (28), or follow-up < 12 months (7 cases) were excluded (446 patients with 563 tumors). Patients who had received radiosurgery for a presumed meningioma without histological confirmation were classified as having benign meningiomas. The preradio-surgery history, imaging, treatment plan, and follow-up duration were obtained using the computer database for the remaining 116 patients (35 men and 81 women). The average patient age was 60 years (range 20–84 years). Seventy-four patients (64%) had undergone prior surgery. The average time from resection to SRS was 53.7 months (range 1–240 months). The tumor locations are outlined in Table 1.

Stereotactic RadiosurgeryRadiosurgery at our institution was performed with

the Leksell Gamma Knife (Elekta Instruments). Dose planning was performed using MR imaging whenever possible. Multiple-shot dose plans were typically used for conformal irradiation of the enhancing tumor. The mean number of isocenters was 12.9 (range 5–27). The radiation dose was prescribed to the 50% isodose line for 102 tumors (88%). The mean PIV was 17.5 cm3 (range 10.1–48.6 cm3). The mean tumor margin dose was 15.1 Gy (range 12–18 Gy) and the mean maximum radiation dose was 31.1 Gy (range 24–36 Gy).

Follow-Up and Statistical AnalysisMagnetic resonance imaging was typically obtained

at 6, 12, and 24 months from the date of the operation. If the tumor remained stable at 24 months, MR imaging was then recommended every 24–36 months. Tumor size in the x, y, and z planes and regions of increased signal on long-TR sequences were recorded on follow-up MR images and compared with the day of SRS for evidence of tumor progression or adverse radiation-related ef-fects. Tumor enlargement > 2 mm was considered lesion growth, and new tumor formation away from the PIV was coded as a marginal recurrence. Other imaging features that were considered were cyst formation, and stenosis or occlusion of adjacent major arteries.

The follow-up neurological examination was per-formed at either our institution or by the patient’s local physician. All new neurological deficits occurring after SRS were recorded. Each deficit was classified as minor (no change in the functional status of the patient) or major (impaired functional status). The mean follow-up dura-tion after SRS was 70.1 months (range 12–199 months).

Patient survival, tumor control, and complication

rates were determined using the Kaplan-Meier method. Univariate testing was performed using the log-rank test on the following variables: sex, prior surgery, tumor lo-cation (supratentorial compared with skull base), PIV, number of isocenters, PIV/number of isocenters, tumor margin radiation dose, and maximum radiation dose. Fac-tors with a value of p ≤ 0.10 on univariate testing were placed into a Cox proportional hazards model. All statis-tical tests were 2-tailed, and statistical significance was determined at p < 0.05.

ResultsPatient Survival

Ten patients (9%) died during the follow-up period. Two patients (2%) died of tumor-related causes; one died of cardiac complications 1 month after resection for tu-mor growth that occurred 40 months after radiosurgery, and the second patient died at 62 months of an intracere-bral hemorrhage into a region of radiation necrosis adja-cent to the irradiated meningioma. The other 8 patients (7%) died of unrelated causes.

Imaging OutcomesFive patients (4%) had either in-field (1 patient) or

marginal (4) tumor progression detected at a median of 40 months (range 16–84 months) after radiosurgery. One patient underwent resection after SRS for tumor progres-sion, and 2 underwent repeat radiosurgery. Two patients have been followed without further tumor-directed thera-py. The overall 3- and 7-year tumor control rates were 99 and 92%, respectively. The in-field 3- and 7-year tumor control rates were 100 and 98%, respectively. No factor was associated with tumor growth after SRS.

Postradiosurgical edema was noted in 16 patients (14%) (Fig. 1). Seven patients (6%) were symptomatic and received corticosteroid therapy. One patient did not re-spond to corticosteroid therapy and underwent resection

TABLE 1: Tumor locations in 116 patients who underwent SRS for meningiomas

Location No. of Patients (%)

skull base 91 (78) cavernous sinus 52 (45) petroclival 11 (10) cerebellopontine angle 8 (7) sphenoid wing 8 (7) foramen magnum 5 (4) tentorium 5 (4) anterior fossa 2 (2)supratentorial 25 (22) parasagittal 13 (11) falx 7 (6) convexity 5 (4)


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of the tumor and adjacent necrotic brain. Three patients developed asymptomatic cysts. Stenosis (in 1 patient) or occlusion (in 2) of the ICA was seen in 3 patients after SRS for cavernous sinus meningiomas. One patient had a ce-rebral infarction 39 months after SRS, whereas 2 patients were asymptomatic. One patient had a pontine infarction 8 months after SRS of a petroclival meningioma.

Postradiosurgical Complications

Fourteen of 78 patients with preexisting neurologi-cal deficits improved after SRS. Twenty-seven patients (23%) developed complications after SRS, as outlined in Table 2. The median time to complications was 7 months (range 1 day–99 months) after SRS. The complications were classified as major in 8 patients (7%) and minor in 19 patients (16%). Complications by specific tumor loca-tion are shown in Table 3.

Univariate analysis found male sex (34% versus 17%) (HR 2.4, 95% CI 1.2–5.3, p = 0.02) and supratentorial tu-mor location (44% versus 18%) (HR 3.6, 95% CI 1.6–7.8, p = 0.001) as risk factors for postradiosurgical complica-tions (Table 4). Multivariate analysis showed that patients with supratentorial tumors experienced a higher compli-cation rate compared with patients with skull base tumors (HR 2.9, 95% CI 1.3–6.7, p = 0.01) (Fig. 2). Subset analy-sis of the supratentorial tumors with PIV as a continuous variable showed a positive correlation between treatment volume and the risk of postradiosurgical complications (HR 1.06, 95% CI 1.0–1.12, p = 0.04). The risk of com-plications per quartile was as follows: < 13.4 cm3 (1 of 6, 17%), 13.4–15.7 cm3 (2 of 7, 29%), 15.8–19.7 cm3 (4 of 6, 67%), and > 19.7 cm3 (4 of 6, 67%). Five (71%) of 7 patients with parasagittal tumors involving the middle third of the superior sagittal sinus had complications, compared with 2 (33%) of 6 patients with parasagittal tumors adjacent to the posterior third of the superior sagittal sinus (p = 0.29).

DiscussionStereotactic radiosurgery is an accepted treatment

option for many patients with intracranial meningiomas. With the advent of improved and more frequent imag-ing, small meningiomas are often diagnosed in patients with cranial nerve dysfunction, headaches, and as inci-dental findings. The fact that meningiomas are typically well visualized on MR imaging and do not invade into the adjacent brain permits complete radiation coverage of the neoplastic cells. In addition, the radiobiological advantage of dose fractionation for benign tumors, con-sidered a late-responding tissue, is much less than for rapidly dividing, malignant tumors. These considerations are highlighted by the fact that the 2 primary factors as-sociated with failed meningioma radiosurgery are tumor grade and prior surgery.12,19 Nonetheless, radiosurgery is generally considered the preferred management option for patients with small to moderate-sized skull base men-ingiomas and for patients with recurrent or enlarging re-sidual tumors after prior resection.

Based on the experience of radiosurgery for patients

Fig. 1. Axial long-TR MR images obtained in a 78-year-old woman with Parkinson disease with an enlarging right parietal convexity meningioma. A: Admission MR image obtained before radiosurgery. At radiosurgery the PIV was 12.2 cm3; the tumor margin dose was 16 Gy. B: Follow-up MR image obtained 11 months after radiosurgery. The patient developed left-sided weak-ness and partial motor seizures requiring corticosteroid therapy for 9 months. C: Follow-up MR image obtained 9 years after radiosurgery showing a reduction in tumor size and resolution of the surrounding edema.

TABLE 2: Complications after radiosurgery in 27 patients*

Complication No. of Patients (%)seizure 7 (6)hemiparesis 6 (5)trigeminal dysfunction 5 (4)headache 4 (3)diplopia 3 (3)cerebral infarction 2 (2)ataxia 2 (2)hearing loss 1 (1)

* Some patients had > 1 complication.



with skull base meningiomas, more patients with con-vexity and parasagittal tumors are undergoing SRS each year. Kim et al.8 performed radiosurgery for 23 patients (26 tumors) with superficially located meningiomas. The median tumor volume in their series was 4.7 cm3, and the tumor margin dose was 16 Gy. Increased or new peritu-moral edema was noted 11 (42%) of 26 tumors, and was symptomatic in 10 patients (severe headache in 7; severe headache and hemiparesis in 3). Five patients required corticosteroid therapy. No patient had a new permanent deficit after radiosurgery. Kondziolka et al.11 recently re-viewed 125 patients who underwent GKS for convexity meningiomas. One hundred four patients either had his-tologically proven WHO Grade I tumors or were treated primarily. The majority of these (82 patients; 79%) had tumors < 10 cm3 in volume, and the radiation dose to the tumor margin ranged from 10 Gy to > 15 Gy. At a median follow-up of 31 months, 97% of patients with recurrent/residual tumors and 92% of patients who had undergone primary radiosurgery had tumor growth control. Multi-variate analysis of the entire cohort found that disease-specific survival was worse with patients with WHO Grade II or III tumors and increasing tumor volume. Complication-free survival was associated with smaller tumor volumes and the absence of prior radiotherapy. Patil et al.17 reviewed 102 patients (111 tumors) who had undergone CyberKnife radiosurgery for supratentorial meningiomas. Seventy-four tumors (67%) were < 6 cm3 in volume. Forty-five tumors (41%) were treated in 2 or more sessions. Seventy-nine tumors (71%) received 16 Gy or more when considered as a single-session equivalent dose. At a median follow-up of 15 months, 15 patients (15%) had developed symptomatic edema after SRS. Pa-tients with parasagittal meningiomas were 4.1 times more likely to develop symptomatic edema than patients with nonmidline supratentorial tumors. Patients with parasag-ittal meningiomas had a 35% actuarial risk of developing symptomatic edema 18 months after SRS.

In addition to treating meningiomas in surgically

treatable locations, the progressive trend to use lower ra-diation doses for benign tumors has encouraged the use of radiosurgery for the treatment of larger lesions. Iwai and colleagues7 reported the results of low-dose GKS to treat patients with skull base meningiomas. Between 1994 and 2001, 108 patients underwent SRS in which a median tu-mor margin dose of 12 Gy was used. The median tumor volume was 8.1 cm3. Local tumor growth was noted in 7 patients (6%) at a median of 86 months, and 5 additional patients suffered a marginal recurrence. Seven patients (6%) had a permanent radiation-related complication af-ter SRS, most commonly a new cranial nerve deficit. One patient had a cerebral infarction secondary to a middle cerebral artery perforating vessel occlusion. Three pa-tients had intratumoral bleeding: 1 of them died of this complication.

In our series we performed GKS in 116 patients with benign meningiomas > 10 cm3 in volume (mean 17.5 cm3). The mean tumor margin radiation dose was 15.1 Gy. The overall 3- and 7-year tumor control rates were 99 and 92%, respectively. Major complications occurred in 8 patients (7%), and were more common for patients with supratentorial tumors compared with those with skull base tumors. Like the series of Patil et al.,17 patients with parasagittal tumors had a higher incidence of neuro-logical complications compared with other supratentorial tumors (54% versus 25%), but this did not reach statistical significance (p = 0.14). Importantly, our tumor volumes were significantly greater than in that series (mean vol-ume 17.5 cm3 compared with 5.6 cm3). Of note, our in-field tumor control rate after using tumor margin doses of 14–15 Gy was 98% at 7 years, considerably higher than that reported by Iwai et al.,7 who used a tumor margin dose of 12 Gy, and is completely in accordance with the recent large series from the University of Pittsburgh on meningioma radiosurgery.12 Using a mean tumor margin dose of 14 Gy, their overall tumor control rate for WHO Grade I tumors was 93%. Tumor control in patients with-out histological confirmation was 97%. The most com-mon complications we noted for these large skull base tumors were new trigeminal dysfunction or diplopia, and we had no patients with symptomatic brainstem edema after radiosurgery.

TABLE 3: Complications by tumor location in 116 patients with meningiomas

Location No. of Patients No. w/ Complications (%)skull base 91 16 (18) cavernous sinus 52 11 (21) petroclival 11 2 (18) cerebellopontine angle 8 1 (13) sphenoid wing 8 0 foramen magnum 5 0 tentorium 5 1 (20) anterior fossa 2 1 (50)supratentorial 25 11 (44) parasagittal 13 7 (54) falx 7 3 (43) convexity 5 1 (20)

TABLE 4: Analysis of factors associated with postradiosurgical complications

Factor HR 95% CI p Valuesex 2.44 1.15–5.26 0.02age 1.02 0.99–1.04 0.26location 3.57 1.64–7.81 0.001prior op 1.29 0.56–2.97 0.54PIV 1.00 1.00–1.01 0.46margin dose 1.00 1.00–1.01 0.56max dose 0.99 0.98–1.01 0.56no. of isocenters 0.98 0.89–1.08 0.73PIV/no. of isocenters 1.00 0.99–1.01 0.41


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Because a large portion of skull base tumors are not in direct contact with the brain, the overall radiation ex-posure is lower compared with supratentorial locations. Therefore, the need for tumor debulking prior to SRS for patients with skull base tumors is relatively rare in our experience. Conversely, the high complication rate we have noted for the other tumor locations has profoundly changed our opinion regarding the use of SRS to treat pa-tients with larger supratentorial meningiomas. For these patients, we now recommend surgery whenever feasible as a lower risk management strategy than SRS. Last, 2 patients with skull base meningiomas suffered a cerebral infarction after radiosurgery. Radiation-induced vascular injury has been noted by other groups following menin-gioma radiosurgery,2,7,16 and a case of ICA occlusion has also been reported after radiosurgery in a patient with a pituitary adenoma.15 Limiting the radiation coverage of the adjacent large arteries may decrease the incidence of this complication for patients with skull base tumors, but this is not possible when tumor completely encircles the ICA.

The success of resection of convexity meningiomas is typically taken for granted, and few large series are available for these patients. Kinjo et al.9 noted no surgi-cal morbidity and found no tumor recurrences in a series of 37 patients with convexity meningiomas. Black et al.1 reviewed 163 patients undergoing resection of convex-ity meningiomas between 1986 and 2005. The median maximum tumor diameter was 3.5 cm. Complete tu-mor resection (Simpson Grade 1) was achieved in 95% of the surgeries. The 30-day mortality rate was 0%, and the incidence of new neurological deficits was < 2%. The 5-year recurrence rate was 1.8% for patients with benign meningiomas. Of note, the 2 patients with recurrent be-nign tumors displayed features consistent with borderline atypia and MIB-1 indices of 10 and 17%, respectively. Therefore, although patients with supratentorial tumors less than the median volume (15.8 cm3) had fewer compli-cations compared with patients with larger tumors (23% versus 67%) in our series, the morbidity associated with SRS for supratentorial benign meningiomas > 10 cm3 is higher than in reports on the resection of these tumors.

Consequently, we recommend resection whenever fea-sible for patients with supratentorial meningiomas requir-ing treatment, if the average tumor diameter is > 2.5 cm (~ 10 cm3 in volume) If complete tumor removal is not possible, then SRS can be performed for the residual tu-mor if the histological classification is WHO Grade II or III, or at the time of documented enlargement for patients with a WHO Grade I tumor.

ConclusionsSingle-session radiosurgery can be safely performed

for the majority of patients with larger-volume skull base meningiomas. Conversely, the complication rate of single-session radiosurgery is significantly greater for patients with supratentorial meningiomas. Patients with supraten-torial meningiomas with an estimated volume > 10 cm3 requiring treatment should undergo resection whenever feasible.

Disclaimer

The authors have no conflict of interest with regard to this man uscript.

References

1. Black PM, Morokoff AP, Zauberman J: Surgery for extra-axial tumors of the cerebral convexity and midline. Neuro-surgery 62:1115–1123, 2008

2. Couldwell WT, Cole CD, Al-Mefty O: Patterns of skull base meningioma progression after failed radiosurgery. J Neuro-surg 106:30–35, 2007

3. De Jesus O, Sekhar LN, Parikh HK, Wright DC, Wagner DP: Long-term follow-up of patients with meningiomas involving the cavernous sinus: recurrence, progression, and quality of life. Neurosurgery 39:915–920, 1996

4. DeMonte F, Smith HK, al-Mefty O: Outcome of aggressive removal of cavernous sinus meningiomas. J Neurosurg 81: 245–251, 1994

5. Flickinger JC, Kondziolka D, Pollock BE, Maitz AH, Lunsford LD: Complications from arteriovenous malforma-tion radiosurgery: multivariate analysis and risk modeling. Int J Radiat Oncol Biol Phys 38:485–490, 1997

6. Goldsmith BJ, Wara WM, Wilson CB, Larson DA: Postop-erative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 80:195–201, 1994

7. Iwai Y, Yamanaka K, Ikeda H: Gamma Knife radiosurgery for skull base meningioma: long-term results of low-dose treatment. J Neurosurg 109:804–810, 2008

8. Kim DG, Kim ChH, Chung HT, Paek SH, Jeong SS, Han DH, et al: Gamma knife surgery of superficially located menin-gioma. J Neurosurg 102 (Suppl):255–258, 2005

9. Kinjo T, al-Mefty O, Kanaan I: Grade zero removal of su-pratentorial convexity meningiomas. Neurosurgery 33:394–399, 1993

10. Kondziolka D, Flickinger JC, Perez B: Judicious resection and/or radiosurgery for parasagittal meningiomas: outcomes from a multicenter review. Gamma Knife Meningioma Study Group. Neurosurgery 43:405–414, 1998

11. Kondziolka D, Madhok R, Lunsford LD, Mathieu D, Martin JJ, Niranjan A, et al: Stereotactic radiosurgery for convexity meningiomas. Clinical article. J Neurosurg 111:458–463, 2009 [epub ahead of print January 16, 2009. DOI: 10.3171/ 2008.8.JNS17650]

Fig. 2. Graph comparing the incidence of complications for patients who underwent radiosurgery for supratentorial compared with skull base meningiomas.



12. Kondziolka D, Mathieu D, Lunsford LD, Martin JJ, Madhok R, Niranjan A, et al: Radiosurgery as definitive manage-ment of intracranial meningiomas. Neurosurgery 62:53–60, 2008

13. Kotapka MJ, Kalia KK, Martinez AJ, Sekhar LN: Infiltration of the carotid artery by cavernous sinus meningioma. J Neu-rosurg 81:252–255, 1994

14. Larson JJ, van Loveren HR, Balko MG, Tew JM Jr: Evidence of meningioma infiltration into cranial nerves: clinical impli-cations for cavernous sinus meningiomas. J Neurosurg 83: 596–599, 1995

15. Lim YJ, Leem W, Park JT, Kim TS, Rhee BA, Kim GK: Ce-rebral infarction with ICA occlusion after Gamma Knife ra-diosurgery for pituitary adenoma: a case report. Stereotact Funct Neurosurg 72 (Suppl 1):132–139, 1999

16. Metellus P, Regis J, Muracciole X, Fuentes S, Dufour H, Nanni I, et al: Evaluation of fractionated radiotherapy and gamma knife radiosurgery in cavernous sinus meningiomas: treatment strategy. Neurosurgery 57:873–886, 2005

17. Patil CG, Hoang S, Borchers DJ III, Sakamoto G, Soltys SG,

Gibbs IC, et al: Predictors of peritumoral edema after ste-reotactic radiosurgery of supratentorial meningiomas. Neu-rosurgery 63:435–442, 2008

18. Simpson D: The recurrence of intracranial meningiomas af-ter surgical treatment. J Neurol Neurosurg Psychiatry 20: 22–39, 1957

19. Stafford SL, Pollock BE, Foote RL, Link MJ, Gorman DA, Schomberg PJ, et al: Meningioma radiosurgery: tumor con-trol, outcomes, and complications among 190 consecutive pa-tients. Neurosurgery 49:1029–1038, 2001

Manuscript submitted May 4, 2009.Accepted August 24, 2009.Please include this information when citing this paper: published

online September 18, 2009; DOI: 10.3171/2009.8.JNS09703.Address correspondence to: Bruce E. Pollock, M.D., Department

of Neurological Surgery, Mayo Clinic, Rochester, Minnesota 55905. email: [email protected].

radiosurgery for large-volume (> 10 cm ) benign meningiomas8 months after srs of a petroclival...

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