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Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma

Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma ; ( ): Brain Tumor Res Treat 2015 3 2 103-107 / pISSN 2288-2405 / eISSN 2288-2413 ORIGINAL ARTICLE http://dx.doi.org/10.14791/btrt.2015.3.2.103 Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma Chang Ki Jang, Hyun Ho Jung, Jong Hee Chang, Jin Woo Chang, Yong Gou Park, Won Seok Chang Department of Neurosurgery, Yonsei Gamma Knife Center, Yonsei University College of Medicine, Seoul, Korea Background The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or can- not be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. Methods We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imag- ing, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multi- ple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient’s age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage Received July 20, 2015 was 13.9 Gy. Revised September 3, 2015 Accepted October 8, 2015 The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evi- Results ( ) dence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema PTE after Correspondence gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had Won Seok Chang Department of Neurosurgery, Yonsei craniotomy and tumor removal after gamma knife surgery. Gamma Knife Center, Yonsei University Conclusion Gamma knife surgery for intracranial meningioma has proven to be a safe and effec- College of Medicine, 50-1 Yonsei-ro, tive treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially Seodaemun-gu, Seoul 03722, Korea effective in cases of remnant meningioma after surgical resection or where PTE is not present. Tel: +82-2-2228-2176 Fax: +82-2-393-9979 E-mail: changws0716@yuhs.ac Key Words Meningioma; Radiosurgery; Stereotactic. it has become an important management tool for patients INTRODUCTION with intracranial meningioma. Intracranial meningioma makes up 15–20% of primary At 5 years aer ga ft mma knife surgery, tumor control rates brain tumors and is the most common primary adult brain tu- of 90–100% are reported for intracranial meningioma [6-9]. mor [1]. The predominant treatment of intracranial menin - However, reports on long-term outcomes for meningioma gioma is surgical resection [2,3]. are limited because of its pathologic characteristics; it is most However, tumor recurrence or progression can be a signif- oen b ft enign and so patients do not follow-up at out-patient icant problem aer s ft urgery because of the involvement of ad - departments. jacent cranial nerves or major intracranial arteries. Treatment We reviewed clinical outcomes in 628 consecutive patients of small-size tumors with surgical removal can have compli- with meningioma. cations and may be contentious. In such cases, gamma knife surgery is a feasible alternative treatment modality [4,5]. Thus, MATERIALS AND METHODS This is an Open Access article distributed under the terms of the Creative Commons Patients Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any We studied 628 patients who underwent gamma knife ra- medium, provided the original work is properly cited. diosurgery for intracranial incidental meningioma from Jan Copyright © 2015 The Korean Brain Tumor Society, The Korean Society for Neuro- Oncology, and The Korean Society for Pediatric Neuro-Oncology 2008 to Nov 2012 at the Yonsei University College of Medicine. 103 Long-Term Results of GKS for Meningioma We included patients with single lesion meningioma and were in contraindication. followed up after 6 months with imaging, and then at 24 Data was analyzed using the chi-square, Fisher exact, and months with a clinical examination. The median patient age Kruskal-Wallis tests. Multivariate analysis was carried out us- at the time of gamma knife treatment was 56.8 years (28–83 ing the Cox proportional hazards regression analysis. years). Of the 628 patients, 130 (20%) were male, and 498 (80%) The Statistical Package for the Social Sciences version were female. In cases in which surgery was not performed 20.0.0 (IBM, Armonk, NY, USA) was used for all statistical and histological diagnosis was not obtained, the diagnosis analyses. was confirmed by computed tomography (CT) or magnetic Long-term tumor control and radiation-related complica- resonance imaging (MRI). Clinical follow-up was conducted tion rates were determined using the Kaplan-Meier method. between 1 to 79 months aer ga ft mma knife surgery (median Univariate testing was performed using log rank test. 37 months). Prior resections were performed in 131 patients (20.8%). Institutional Review Board (IRB) approval was ob- RESULTS tained from the severance hospital Yonsei University health system (IRB approval number 4-2015-0604). Clinical follow-up data was available in 628 patients (130 men and 498 women). Histopathological diagnoses was not confirmed in 300 cases and Grade I meningioma was detected Gamma knife technique Tumor locations are listed in Table 1. T1-weighted images in 128 cases. The overall tumor control rate was 95%. Twen - with gadobutrol (Gd, Gadovist; Bayer Schering Pharma AG, ty-eight patients (4%) showed evidence of tumor recurrence. Leverkusen, Germany) enhancement and T2-weighted im- Ninety-eight patients (15%) developed PTE after gamma- ages (repetition time 25, field of view 250 mm, matrix: 256 × knife surgery. Of these, 76 patients were treated with medi- 256 mm). Gamma knife surgery was performed using Leksell cines, and 31 of them fully recovered aer t ft his treatment. Two Gamma Knife type C or Perfexion (Elekta Instrument AB, patients (2%) had surgical resection for PTE. Stockholm, Sweden). Overall, the median progression free survival (PFS) time Patients underwent gamma knife surgery aer a ft pplication was 75 months, and the overall 5-year PFS (5YR PFS) was of local anesthesia for stereotactic head frame. After frame 94.7% (Fig. 1). application, MRI was conducted in the axial plane. Confor- The median PFS for patients older and younger than 65 mal and selective dose plans were created, always using multi- years was 69 and 70.9 months, respectively. The 5YR PFS for ple isocenters. Dose selection was based on individual factors patients older and younger than 65 years was 69.0% and that included age, prior exposure to radiation therapy, tumor 70.9%, respectively (p-value=0.986) (Table 2). volume, tumor location, and neurological status by using the In men, the median PFS was 69.1 months, while it was GammaPlan treatment planning sowa ft re. The median mar - 76.1 months for women (p-value=0.065). The median PFS for ginal and maximal dose delivered to the tumor was 13.9 Gy patients with and without PTE was 85.3 and 96.5 months, re- (range, 9 to 19 Gy) and 27.8 Gy (range, 20 to 36 Gy), respec- spectively. The 5YR PFS of patients with and without PTE was tively. 69.0% and 76.0%, respectively (p-value=0.000) (Table 2). Serial imaging follow-ups were performed using MRI to ex- Gamma Knife radiosurgery was the primary treatment for amine changes in tumor volume, peritumoral edema (PTE), 497 patients (79.2%), while 131 patients (20.8%) had previous- and hydrocephalus; CT was performed when the MRI results Table 1. Demographics for the 628 patients who underwent gam- 1.0 ma knife surgery Factor Total: 628 0.8 Gender Male 130 0.6 Female 498 Age Mean (yr) 56.8±11.3 0.4 Location Supratentorial 179 Middle cranial fossa 143 0.2 Cerebellopontine angle 100 0.0 Parasagittal 97 0.0 20.0 40.0 60.0 80.0 Falx 72 FUD Infratentorial convexity 31 Intraventricular 6 Fig. 1. Overall survival. FUD, follow-up duration (months). 104 Brain Tumor Res Treat 2015;3(2):103-107 CK Jang et al. ly undergone open surgery. The mean period to gamma knife follow-up analysis. surgery aer o ft pen surgery was 40 months (range, 0 to 227 In these few studies, the overall tumor control rates were months). Nine patients underwent craniotomy and tumor –86–100% with minimal complications to vital structures removal aer ga ft mma knife surgery (Table 2). [14,15]. e m Th edial PFS was 77.4 months for patients for whom the Kondziolka et al. [16] reported patient outcomes at up to 10 primary treatment was gamma knife surgery and 62.3 months years aer radios ft urgery and found a tumor control rate of 95%. for those who had previously undergone open surgery. The In a study in which adjacent or new tumor growth away from corresponding values for 5YR PFS were 97.9% and 81.8%. the primary target was considered as treatment failure, the tu- e o Th nly factors showing tendency for survival in the multi - mor control rate dropped to 89% at 10 years [17]. In the Mayo variate analysis was PTE (Table 3). clinic study of larger (>10 mL) benign meningiomas, Bledsoe et al. [18] reported a tumor control rate of 99% at 7 years and a neurological complication rate of 44% in supratentorial tu- DISCUSSION mors and 18% in skull-base tumors. Further, Han et al. [19] Over the last two decades, gamma knife surgery has be- reported outcomes ae ft r gamma knife surgery for 63 skull- come an alternative component in multimodal management based meningiomas treated with a mean marginal isodose of of primary and surgically removed intracranial meningioma. 12.7 Gy. The overall tumor control rate was 90%, with follow- It has been applied frequently in patients in whom the menin- up period ranging from 12 to 60 months. gioma is located in challenging location, for solitary, small In our study, the overall tumor control rate was 95%. Twen- tumors or for patients showing recurrence ae ft r incomplete ty-eight patients (4%) showed evidence of tumor recurrence. resections [10]. It has been demonstrated to be ee ff ctive for Couldwell et al. [20] analyzed patterns for failure aer ga ft m - controlling tumor growth. ma knife surgery for benign meningiomas and reported a Most previous studies reporting gamma knife surgery for higher likelihood of failure in cavernous sinus meningiomas. intracranial meningioma had follow-up periods of fewer than In a recent study, tumor progression aer ga ft mma knife surgery 5 years [7,11-13]. Only few studies have provided long-term was high in patients treated with incomplete coverage, with cavernous sinus or with meningiomatosis, despite benign tu- Table 2. Five-year progression free survival (5YR PFS) and me- mor histology. dial progression free survival (mPFS) of patients with asymptom- atic intracranial meningioma Relatively fewer recurrences have been reported for patients 5YR PFS (%) mPFS (mo) p-value with meningiomas who received higher marginal doses (>14 Age 0.986 Gy) in comparison with those who received lower doses (10– 65> 96.5 69.0 65 94.4 70.9 1.0 Gender 0.065 Male 69.1 Female 76.1 0.8 PTE <0.001 Yes 85.3 69.0 No 96.5 76.0 0.6 Surgery 0.017 Previous done 81.8 62.3 0.4 No 97.9 77.4 PTE, peritumoral edema Table 3. Multivariate analysis 0.2 p-value 95% CI Primary Remnant Age over 65 0.238 0.711 1.089 0.0 Gender 0.086 0.661 1.028 Max dose (Gy) 0.499 0.701 1.189 0.0 20.0 40.0 60.0 80.0 Marginal dose (Gy) 0.112 0.909 2.500 FUD PTE 0.079 0.619 1.027 Fig. 2. Influence of primary surgery or post-surgery remnant le - Location 0.676 0.785 1.308 sion radiation on progression free survival. FUD, follow-up dura- tion (months). CI, confidence interval; PTE, peritumoral edema 105 Long-Term Results of GKS for Meningioma 12 Gy) [14]. higher tumor control rate is unknown, but one hypothesis is Various factors may inu fl ence the long-term outcomes and related to the presence of hormone receptors in meningiomas. likelihood of complications. Kondziolka et al. [16] reported Sexual hormone assays of meningiomas exhibit the presence prior radiation therapy (p<0.0001) and high-grade tumors of estrogen, progesterone, and androgen receptors [21]. Fur- (p<0.0001) as factors associated with a worse PFS. Age, sex, ther, patients treated with less conformal plans to cover the tumor volume, and margin dose were not associated with PFS. dural tail have been reported to have better outcomes. Previ- DiBiase et al. [11] reported that male patients and patients ous studies demonstrate the need to adequately cover the du- with tumor size greater than 10 cc were more likely to have a ral tail in patients treated with gamma knife surgery for be- worse prognosis. The reason for female patients having a nign intracranial meningiomas. Additionally, previous surgery to treat a lesion larger than 10 cc was found to be a significant factor ae ff cting the likelihood of tumor control [11]. Radia - 1.0 tion-related complications were associated with tumor loca- tion (convexity/falx) and large tumor volume [22]. In our study, previous surgery (Fig. 2) and presence of PTE 0.8 (Fig. 3) were identified as factors influencing PFS. So we rec - ommend that primary surgery was needed before perform- 0.6 0.4 0.2 PTE No Yes 0.0 A 0.0 20.0 40.0 60.0 80.0 FUD Fig. 3. Influence of peritumoral edema on progression free sur - vival. FUD, follow-up duration (months). 1.0 0.8 0.6 0.4 0.2 Gender Fig. 5. Magnetic resonance images of a representative case. A Male 62-year-old man received gamma knife surgery for parasagittal Female meningioma with invasion of superior sagittal sinus. A: Axial T1- 0.0 weighted magnetic resonance (MR) image obtained in Dec 2006 showing homogeneous enhancing round mass with invasion of 0.0 20.0 40.0 60.0 80.0 superior sagittal sinus. B: Axial T1-weighted MR image from Aug 2009 (post gamma knife surgery 32 months) showing increased FUD heterogeneous enhancing round mass with aggravated peritu- Fig. 4. Influence of gender on progression free survival. FUD, fol - moral edema. C: Axial T1-weighted MR image from Sep 2009 low-up duration (months). (post-operation) showing no remnant lesion. 106 Brain Tumor Res Treat 2015;3(2):103-107 CK Jang et al. ernous sinus meningiomas. J Neurosurg 2002;97:65-72. ing gamma knife surgery if there is PTE. Male patients tend- 5. Pollock BE, Stao ff rd SL. Results of stereotactic radiosurgery for patients ed to have poorer PFS than female patients (Fig. 4), although with imaging defined cavernous sinus meningiomas. Int J Radiat Oncol this finding did not reach statistical significance. Further, older Biol Phys 2005;62:1427-31. patients (≥65) showed similar long-term tumor control rates 6. Kreil W, Luggin J, Fuchs I, Weigl V, Eustacchio S, Papaefthymiou G. Long term experience of gamma knife radiosurgery for benign skull compared to younger patients (<65). This provides evidence base meningiomas. J Neurol Neurosurg Psychiatry 2005;76:1425-30. that gamma knife surgery for meningioma is plausible even 7. Nicolato A, Foroni R, Alessandrini F, Bricolo A, Gerosa M. Radiosurgi- for elderly patients. The only factor that showed tendency on cal treatment of cavernous sinus meningiomas: experience with 122 treated patients. Neurosurgery 2002;51:1153-9; discussion 1159-61. multivariate analysis was PTE. In this report, patients with- 8. Starke RM, Nguyen JH, Rainey J, et al. Gamma Knife surgery of me- out PTE had a significantly higher 5YR PFS than those with ningiomas located in the posterior fossa: factors predictive of outcome PTE (96.5% vs. 85.3%, p-value<0.001), and this remained and remission. J Neurosurg 2011;114:1399-409. 9. Subach BR, Lunsford LD, Kondziolka D, Maitz AH, Flickinger JC. tendency on multivariate analysis (Table 3). Management of petroclival meningiomas by stereotactic radiosurgery. Our study does have some limitations. It was retrospective Neurosurgery 1998;42:437-43; discussion 443-5. and involved cases that were not confirmed by histopathology. 10. Iwai Y, Yamanaka K, Ikeda H. Gamma Knife radiosurgery for skull Specifically, for 500 cases, histological confirmation was not base meningioma: long-term results of low-dose treatment. J Neurosurg 2008;109:804-10. obtained. Of the 128 cases that were histopathologically con- 11. DiBiase SJ, Kwok Y, Yovino S, et al. Factors predicting local tumor con- firmed, 100 were of World Health Organization (WHO) grade trol aer ga ft mma knife stereotactic radiosurgery for benign intracrani - I, 25 were of WHO grade II, and 3 were of WHO grade III. al meningiomas. Int J Radiat Oncol Biol Phys 2004;60:1515-9. 12. Pendl G, Schröttner O, Eustacchio S, Ganz JC, Feichtinger K. Cavern- A small percentage of meningiomas appear to have malig- ous sinus meningiomas--what is the strategy: upfront or adjuvant nant potential [23,24]. According to the literature on menin- gamma knife surgery? Stereotact Funct Neurosurg 1998;70 Suppl 1:33- gioma, diverse behaviors of the tumors are described. One of 13. Nicolato A, Foroni R, Pellegrino M, et al. Gamma knife radiosurgery our patients, a 62-year-old man, received gamma knife sur- in meningiomas of the posterior fossa. Experience with 62 treated le- gery for a parasagittal meningioma with invasion of the su- sions. Minim Invasive Neurosurg 2001;44:211-7. perior sagittal sinus (Fig. 5A). After 32 months, follow-up 14. Shin M, Kurita H, Sasaki T, et al. Analysis of treatment outcome aer ft with MRI revealed increasing tumor size with PTE (Fig. 5B). stereotactic radiosurgery for cavernous sinus meningiomas. J Neuro- surg 2001;95:435-9. We performed total resection of that lesion, which had atypi- 15. Roche PH, Pellet W, Fuentes S, Thomassin JM, Régis J. Gamma knife cal pathology for meningioma (WHO grade III) (Fig. 5C). radiosurgical management of petroclival meningiomas results and in- According to our results, gamma knife surgery for intracra- dications. Acta Neurochir (Wien) 2003;145:883-8; discussion 888. 16. Kondziolka D, Patel AD, Kano H, Flickinger JC, Lunsford LD. Long- nial meningioma is safe and effective with successful long- term Outcomes Aer Ga ft mma Knife Radiosurgery for Meningiomas. term outcomes. It can be a highly effective treatment modali - Am J Clin Oncol 2014 Apr 21. [Epub] ty particularly in cases of remnant meningioma aer s ft urgical 17. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. Gamma knife radiosurgery of imaging-diagnosed intracranial meningioma. Int J resection as well as in cases without PTE. Radiat Oncol Biol Phys 2003;56:801-6. 18. Bledsoe JM, Link MJ, Stao ff rd SL, Park PJ, Pollock BE. Radiosurgery Conflicts of Interest for large-volume (> 10 cm3) benign meningiomas. J Neurosurg e a Th uthors have no financial conflicts of interest. 2010;112:951-6. 19. Han JH, Kim DG, Chung HT, et al. Gamma knife radiosurgery for Acknowledgments skull base meningiomas: long-term radiologic and clinical outcome. This work was supported by The Yonsei University Future-leading Re - Int J Radiat Oncol Biol Phys 2008;72:1324-32. search Initiative (Yonsei Challenge) of 2014 (2014-22-0150) and Basic Sci- 20. Couldwell WT, Cole CD, Al-Mefty O. Patterns of skull base meningio - ence Research Program through the National Research Foundation of Ko- ma progression aer fa ft iled radiosurgery. J Neurosurg 2007;106:30-5. rea (NRF) funded by the Ministry of Science, ICT and Future Planning 21. Goodwin JW, Crowley J, Eyre HJ, Stao ff rd B, Jaeckle KA, Townsend JJ. (2015R1C1A1A02036851). A phase II evaluation of tamoxifen in unresectable or refractory me- ningiomas: a Southwest Oncology Group study. J Neurooncol 1993; 15:75-7. REFERENCES 22. Pollock BE, Stao ff rd SL, Link MJ, Garces YI, Foote RL. Single-fraction 1. Claus EB, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M, Black radiosurgery for presumed intracranial meningiomas: efficacy and PM. Epidemiology of intracranial meningioma. Neurosurgery 2005; complications from a 22-year experience. Int J Radiat Oncol Biol Phys 57:1088-95; discussion 1088-95. 2012;83:1414-8. 2. Sanna M, Bacciu A, Falcioni M, Taibah A, Piazza P. Surgical manage- 23. Jääskeläinen J, Haltia M, Servo A. Atypical and anaplastic meningio- ment of jugular foramen meningiomas: a series of 13 cases and review mas: radiology, surgery, radiotherapy, and outcome. Surg Neurol 1986; of the literature. Laryngoscope 2007;117:1710-9. 25:233-42. 3. Voss NF, Vrionis FD, Heilman CB, Robertson JH. Meningiomas of the 24. Modha A, Gutin PH. Diagnosis and treatment of atypical and anaplas- cerebellopontine angle. Surg Neurol 2000;53:439-46; discussion 446-7. tic meningiomas: a review. Neurosurgery 2005;57:538-50; discussion 4. Lee JY, Niranjan A, McInerney J, Kondziolka D, Flickinger JC, Lunsford 538-50. LD. Stereotactic radiosurgery providing long-term tumor control of cav- http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Tumor Research and Treatment Pubmed Central

Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma

Brain Tumor Research and Treatment , Volume 3 (2) – Oct 30, 2015

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Copyright © 2015 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology
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Abstract

; ( ): Brain Tumor Res Treat 2015 3 2 103-107 / pISSN 2288-2405 / eISSN 2288-2413 ORIGINAL ARTICLE http://dx.doi.org/10.14791/btrt.2015.3.2.103 Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma Chang Ki Jang, Hyun Ho Jung, Jong Hee Chang, Jin Woo Chang, Yong Gou Park, Won Seok Chang Department of Neurosurgery, Yonsei Gamma Knife Center, Yonsei University College of Medicine, Seoul, Korea Background The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or can- not be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. Methods We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imag- ing, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multi- ple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient’s age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage Received July 20, 2015 was 13.9 Gy. Revised September 3, 2015 Accepted October 8, 2015 The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evi- Results ( ) dence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema PTE after Correspondence gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had Won Seok Chang Department of Neurosurgery, Yonsei craniotomy and tumor removal after gamma knife surgery. Gamma Knife Center, Yonsei University Conclusion Gamma knife surgery for intracranial meningioma has proven to be a safe and effec- College of Medicine, 50-1 Yonsei-ro, tive treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially Seodaemun-gu, Seoul 03722, Korea effective in cases of remnant meningioma after surgical resection or where PTE is not present. Tel: +82-2-2228-2176 Fax: +82-2-393-9979 E-mail: changws0716@yuhs.ac Key Words Meningioma; Radiosurgery; Stereotactic. it has become an important management tool for patients INTRODUCTION with intracranial meningioma. Intracranial meningioma makes up 15–20% of primary At 5 years aer ga ft mma knife surgery, tumor control rates brain tumors and is the most common primary adult brain tu- of 90–100% are reported for intracranial meningioma [6-9]. mor [1]. The predominant treatment of intracranial menin - However, reports on long-term outcomes for meningioma gioma is surgical resection [2,3]. are limited because of its pathologic characteristics; it is most However, tumor recurrence or progression can be a signif- oen b ft enign and so patients do not follow-up at out-patient icant problem aer s ft urgery because of the involvement of ad - departments. jacent cranial nerves or major intracranial arteries. Treatment We reviewed clinical outcomes in 628 consecutive patients of small-size tumors with surgical removal can have compli- with meningioma. cations and may be contentious. In such cases, gamma knife surgery is a feasible alternative treatment modality [4,5]. Thus, MATERIALS AND METHODS This is an Open Access article distributed under the terms of the Creative Commons Patients Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any We studied 628 patients who underwent gamma knife ra- medium, provided the original work is properly cited. diosurgery for intracranial incidental meningioma from Jan Copyright © 2015 The Korean Brain Tumor Society, The Korean Society for Neuro- Oncology, and The Korean Society for Pediatric Neuro-Oncology 2008 to Nov 2012 at the Yonsei University College of Medicine. 103 Long-Term Results of GKS for Meningioma We included patients with single lesion meningioma and were in contraindication. followed up after 6 months with imaging, and then at 24 Data was analyzed using the chi-square, Fisher exact, and months with a clinical examination. The median patient age Kruskal-Wallis tests. Multivariate analysis was carried out us- at the time of gamma knife treatment was 56.8 years (28–83 ing the Cox proportional hazards regression analysis. years). Of the 628 patients, 130 (20%) were male, and 498 (80%) The Statistical Package for the Social Sciences version were female. In cases in which surgery was not performed 20.0.0 (IBM, Armonk, NY, USA) was used for all statistical and histological diagnosis was not obtained, the diagnosis analyses. was confirmed by computed tomography (CT) or magnetic Long-term tumor control and radiation-related complica- resonance imaging (MRI). Clinical follow-up was conducted tion rates were determined using the Kaplan-Meier method. between 1 to 79 months aer ga ft mma knife surgery (median Univariate testing was performed using log rank test. 37 months). Prior resections were performed in 131 patients (20.8%). Institutional Review Board (IRB) approval was ob- RESULTS tained from the severance hospital Yonsei University health system (IRB approval number 4-2015-0604). Clinical follow-up data was available in 628 patients (130 men and 498 women). Histopathological diagnoses was not confirmed in 300 cases and Grade I meningioma was detected Gamma knife technique Tumor locations are listed in Table 1. T1-weighted images in 128 cases. The overall tumor control rate was 95%. Twen - with gadobutrol (Gd, Gadovist; Bayer Schering Pharma AG, ty-eight patients (4%) showed evidence of tumor recurrence. Leverkusen, Germany) enhancement and T2-weighted im- Ninety-eight patients (15%) developed PTE after gamma- ages (repetition time 25, field of view 250 mm, matrix: 256 × knife surgery. Of these, 76 patients were treated with medi- 256 mm). Gamma knife surgery was performed using Leksell cines, and 31 of them fully recovered aer t ft his treatment. Two Gamma Knife type C or Perfexion (Elekta Instrument AB, patients (2%) had surgical resection for PTE. Stockholm, Sweden). Overall, the median progression free survival (PFS) time Patients underwent gamma knife surgery aer a ft pplication was 75 months, and the overall 5-year PFS (5YR PFS) was of local anesthesia for stereotactic head frame. After frame 94.7% (Fig. 1). application, MRI was conducted in the axial plane. Confor- The median PFS for patients older and younger than 65 mal and selective dose plans were created, always using multi- years was 69 and 70.9 months, respectively. The 5YR PFS for ple isocenters. Dose selection was based on individual factors patients older and younger than 65 years was 69.0% and that included age, prior exposure to radiation therapy, tumor 70.9%, respectively (p-value=0.986) (Table 2). volume, tumor location, and neurological status by using the In men, the median PFS was 69.1 months, while it was GammaPlan treatment planning sowa ft re. The median mar - 76.1 months for women (p-value=0.065). The median PFS for ginal and maximal dose delivered to the tumor was 13.9 Gy patients with and without PTE was 85.3 and 96.5 months, re- (range, 9 to 19 Gy) and 27.8 Gy (range, 20 to 36 Gy), respec- spectively. The 5YR PFS of patients with and without PTE was tively. 69.0% and 76.0%, respectively (p-value=0.000) (Table 2). Serial imaging follow-ups were performed using MRI to ex- Gamma Knife radiosurgery was the primary treatment for amine changes in tumor volume, peritumoral edema (PTE), 497 patients (79.2%), while 131 patients (20.8%) had previous- and hydrocephalus; CT was performed when the MRI results Table 1. Demographics for the 628 patients who underwent gam- 1.0 ma knife surgery Factor Total: 628 0.8 Gender Male 130 0.6 Female 498 Age Mean (yr) 56.8±11.3 0.4 Location Supratentorial 179 Middle cranial fossa 143 0.2 Cerebellopontine angle 100 0.0 Parasagittal 97 0.0 20.0 40.0 60.0 80.0 Falx 72 FUD Infratentorial convexity 31 Intraventricular 6 Fig. 1. Overall survival. FUD, follow-up duration (months). 104 Brain Tumor Res Treat 2015;3(2):103-107 CK Jang et al. ly undergone open surgery. The mean period to gamma knife follow-up analysis. surgery aer o ft pen surgery was 40 months (range, 0 to 227 In these few studies, the overall tumor control rates were months). Nine patients underwent craniotomy and tumor –86–100% with minimal complications to vital structures removal aer ga ft mma knife surgery (Table 2). [14,15]. e m Th edial PFS was 77.4 months for patients for whom the Kondziolka et al. [16] reported patient outcomes at up to 10 primary treatment was gamma knife surgery and 62.3 months years aer radios ft urgery and found a tumor control rate of 95%. for those who had previously undergone open surgery. The In a study in which adjacent or new tumor growth away from corresponding values for 5YR PFS were 97.9% and 81.8%. the primary target was considered as treatment failure, the tu- e o Th nly factors showing tendency for survival in the multi - mor control rate dropped to 89% at 10 years [17]. In the Mayo variate analysis was PTE (Table 3). clinic study of larger (>10 mL) benign meningiomas, Bledsoe et al. [18] reported a tumor control rate of 99% at 7 years and a neurological complication rate of 44% in supratentorial tu- DISCUSSION mors and 18% in skull-base tumors. Further, Han et al. [19] Over the last two decades, gamma knife surgery has be- reported outcomes ae ft r gamma knife surgery for 63 skull- come an alternative component in multimodal management based meningiomas treated with a mean marginal isodose of of primary and surgically removed intracranial meningioma. 12.7 Gy. The overall tumor control rate was 90%, with follow- It has been applied frequently in patients in whom the menin- up period ranging from 12 to 60 months. gioma is located in challenging location, for solitary, small In our study, the overall tumor control rate was 95%. Twen- tumors or for patients showing recurrence ae ft r incomplete ty-eight patients (4%) showed evidence of tumor recurrence. resections [10]. It has been demonstrated to be ee ff ctive for Couldwell et al. [20] analyzed patterns for failure aer ga ft m - controlling tumor growth. ma knife surgery for benign meningiomas and reported a Most previous studies reporting gamma knife surgery for higher likelihood of failure in cavernous sinus meningiomas. intracranial meningioma had follow-up periods of fewer than In a recent study, tumor progression aer ga ft mma knife surgery 5 years [7,11-13]. Only few studies have provided long-term was high in patients treated with incomplete coverage, with cavernous sinus or with meningiomatosis, despite benign tu- Table 2. Five-year progression free survival (5YR PFS) and me- mor histology. dial progression free survival (mPFS) of patients with asymptom- atic intracranial meningioma Relatively fewer recurrences have been reported for patients 5YR PFS (%) mPFS (mo) p-value with meningiomas who received higher marginal doses (>14 Age 0.986 Gy) in comparison with those who received lower doses (10– 65> 96.5 69.0 65 94.4 70.9 1.0 Gender 0.065 Male 69.1 Female 76.1 0.8 PTE <0.001 Yes 85.3 69.0 No 96.5 76.0 0.6 Surgery 0.017 Previous done 81.8 62.3 0.4 No 97.9 77.4 PTE, peritumoral edema Table 3. Multivariate analysis 0.2 p-value 95% CI Primary Remnant Age over 65 0.238 0.711 1.089 0.0 Gender 0.086 0.661 1.028 Max dose (Gy) 0.499 0.701 1.189 0.0 20.0 40.0 60.0 80.0 Marginal dose (Gy) 0.112 0.909 2.500 FUD PTE 0.079 0.619 1.027 Fig. 2. Influence of primary surgery or post-surgery remnant le - Location 0.676 0.785 1.308 sion radiation on progression free survival. FUD, follow-up dura- tion (months). CI, confidence interval; PTE, peritumoral edema 105 Long-Term Results of GKS for Meningioma 12 Gy) [14]. higher tumor control rate is unknown, but one hypothesis is Various factors may inu fl ence the long-term outcomes and related to the presence of hormone receptors in meningiomas. likelihood of complications. Kondziolka et al. [16] reported Sexual hormone assays of meningiomas exhibit the presence prior radiation therapy (p<0.0001) and high-grade tumors of estrogen, progesterone, and androgen receptors [21]. Fur- (p<0.0001) as factors associated with a worse PFS. Age, sex, ther, patients treated with less conformal plans to cover the tumor volume, and margin dose were not associated with PFS. dural tail have been reported to have better outcomes. Previ- DiBiase et al. [11] reported that male patients and patients ous studies demonstrate the need to adequately cover the du- with tumor size greater than 10 cc were more likely to have a ral tail in patients treated with gamma knife surgery for be- worse prognosis. The reason for female patients having a nign intracranial meningiomas. Additionally, previous surgery to treat a lesion larger than 10 cc was found to be a significant factor ae ff cting the likelihood of tumor control [11]. Radia - 1.0 tion-related complications were associated with tumor loca- tion (convexity/falx) and large tumor volume [22]. In our study, previous surgery (Fig. 2) and presence of PTE 0.8 (Fig. 3) were identified as factors influencing PFS. So we rec - ommend that primary surgery was needed before perform- 0.6 0.4 0.2 PTE No Yes 0.0 A 0.0 20.0 40.0 60.0 80.0 FUD Fig. 3. Influence of peritumoral edema on progression free sur - vival. FUD, follow-up duration (months). 1.0 0.8 0.6 0.4 0.2 Gender Fig. 5. Magnetic resonance images of a representative case. A Male 62-year-old man received gamma knife surgery for parasagittal Female meningioma with invasion of superior sagittal sinus. A: Axial T1- 0.0 weighted magnetic resonance (MR) image obtained in Dec 2006 showing homogeneous enhancing round mass with invasion of 0.0 20.0 40.0 60.0 80.0 superior sagittal sinus. B: Axial T1-weighted MR image from Aug 2009 (post gamma knife surgery 32 months) showing increased FUD heterogeneous enhancing round mass with aggravated peritu- Fig. 4. Influence of gender on progression free survival. FUD, fol - moral edema. C: Axial T1-weighted MR image from Sep 2009 low-up duration (months). (post-operation) showing no remnant lesion. 106 Brain Tumor Res Treat 2015;3(2):103-107 CK Jang et al. ernous sinus meningiomas. J Neurosurg 2002;97:65-72. ing gamma knife surgery if there is PTE. Male patients tend- 5. Pollock BE, Stao ff rd SL. Results of stereotactic radiosurgery for patients ed to have poorer PFS than female patients (Fig. 4), although with imaging defined cavernous sinus meningiomas. Int J Radiat Oncol this finding did not reach statistical significance. Further, older Biol Phys 2005;62:1427-31. patients (≥65) showed similar long-term tumor control rates 6. Kreil W, Luggin J, Fuchs I, Weigl V, Eustacchio S, Papaefthymiou G. Long term experience of gamma knife radiosurgery for benign skull compared to younger patients (<65). This provides evidence base meningiomas. J Neurol Neurosurg Psychiatry 2005;76:1425-30. that gamma knife surgery for meningioma is plausible even 7. Nicolato A, Foroni R, Alessandrini F, Bricolo A, Gerosa M. Radiosurgi- for elderly patients. The only factor that showed tendency on cal treatment of cavernous sinus meningiomas: experience with 122 treated patients. Neurosurgery 2002;51:1153-9; discussion 1159-61. multivariate analysis was PTE. In this report, patients with- 8. Starke RM, Nguyen JH, Rainey J, et al. Gamma Knife surgery of me- out PTE had a significantly higher 5YR PFS than those with ningiomas located in the posterior fossa: factors predictive of outcome PTE (96.5% vs. 85.3%, p-value<0.001), and this remained and remission. J Neurosurg 2011;114:1399-409. 9. Subach BR, Lunsford LD, Kondziolka D, Maitz AH, Flickinger JC. tendency on multivariate analysis (Table 3). Management of petroclival meningiomas by stereotactic radiosurgery. Our study does have some limitations. It was retrospective Neurosurgery 1998;42:437-43; discussion 443-5. and involved cases that were not confirmed by histopathology. 10. Iwai Y, Yamanaka K, Ikeda H. Gamma Knife radiosurgery for skull Specifically, for 500 cases, histological confirmation was not base meningioma: long-term results of low-dose treatment. J Neurosurg 2008;109:804-10. obtained. Of the 128 cases that were histopathologically con- 11. DiBiase SJ, Kwok Y, Yovino S, et al. Factors predicting local tumor con- firmed, 100 were of World Health Organization (WHO) grade trol aer ga ft mma knife stereotactic radiosurgery for benign intracrani - I, 25 were of WHO grade II, and 3 were of WHO grade III. al meningiomas. Int J Radiat Oncol Biol Phys 2004;60:1515-9. 12. Pendl G, Schröttner O, Eustacchio S, Ganz JC, Feichtinger K. Cavern- A small percentage of meningiomas appear to have malig- ous sinus meningiomas--what is the strategy: upfront or adjuvant nant potential [23,24]. According to the literature on menin- gamma knife surgery? Stereotact Funct Neurosurg 1998;70 Suppl 1:33- gioma, diverse behaviors of the tumors are described. One of 13. Nicolato A, Foroni R, Pellegrino M, et al. Gamma knife radiosurgery our patients, a 62-year-old man, received gamma knife sur- in meningiomas of the posterior fossa. Experience with 62 treated le- gery for a parasagittal meningioma with invasion of the su- sions. Minim Invasive Neurosurg 2001;44:211-7. perior sagittal sinus (Fig. 5A). After 32 months, follow-up 14. Shin M, Kurita H, Sasaki T, et al. Analysis of treatment outcome aer ft with MRI revealed increasing tumor size with PTE (Fig. 5B). stereotactic radiosurgery for cavernous sinus meningiomas. J Neuro- surg 2001;95:435-9. We performed total resection of that lesion, which had atypi- 15. Roche PH, Pellet W, Fuentes S, Thomassin JM, Régis J. Gamma knife cal pathology for meningioma (WHO grade III) (Fig. 5C). radiosurgical management of petroclival meningiomas results and in- According to our results, gamma knife surgery for intracra- dications. Acta Neurochir (Wien) 2003;145:883-8; discussion 888. 16. Kondziolka D, Patel AD, Kano H, Flickinger JC, Lunsford LD. Long- nial meningioma is safe and effective with successful long- term Outcomes Aer Ga ft mma Knife Radiosurgery for Meningiomas. term outcomes. It can be a highly effective treatment modali - Am J Clin Oncol 2014 Apr 21. [Epub] ty particularly in cases of remnant meningioma aer s ft urgical 17. Flickinger JC, Kondziolka D, Maitz AH, Lunsford LD. Gamma knife radiosurgery of imaging-diagnosed intracranial meningioma. Int J resection as well as in cases without PTE. Radiat Oncol Biol Phys 2003;56:801-6. 18. Bledsoe JM, Link MJ, Stao ff rd SL, Park PJ, Pollock BE. Radiosurgery Conflicts of Interest for large-volume (> 10 cm3) benign meningiomas. J Neurosurg e a Th uthors have no financial conflicts of interest. 2010;112:951-6. 19. Han JH, Kim DG, Chung HT, et al. Gamma knife radiosurgery for Acknowledgments skull base meningiomas: long-term radiologic and clinical outcome. This work was supported by The Yonsei University Future-leading Re - Int J Radiat Oncol Biol Phys 2008;72:1324-32. search Initiative (Yonsei Challenge) of 2014 (2014-22-0150) and Basic Sci- 20. Couldwell WT, Cole CD, Al-Mefty O. Patterns of skull base meningio - ence Research Program through the National Research Foundation of Ko- ma progression aer fa ft iled radiosurgery. J Neurosurg 2007;106:30-5. rea (NRF) funded by the Ministry of Science, ICT and Future Planning 21. Goodwin JW, Crowley J, Eyre HJ, Stao ff rd B, Jaeckle KA, Townsend JJ. (2015R1C1A1A02036851). A phase II evaluation of tamoxifen in unresectable or refractory me- ningiomas: a Southwest Oncology Group study. J Neurooncol 1993; 15:75-7. REFERENCES 22. Pollock BE, Stao ff rd SL, Link MJ, Garces YI, Foote RL. Single-fraction 1. Claus EB, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M, Black radiosurgery for presumed intracranial meningiomas: efficacy and PM. Epidemiology of intracranial meningioma. Neurosurgery 2005; complications from a 22-year experience. Int J Radiat Oncol Biol Phys 57:1088-95; discussion 1088-95. 2012;83:1414-8. 2. Sanna M, Bacciu A, Falcioni M, Taibah A, Piazza P. Surgical manage- 23. Jääskeläinen J, Haltia M, Servo A. 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Published: Oct 30, 2015

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