Abstract
Malignant meningioma is a rare, aggressive form of meningioma. Radiation is commonly included in treatment guidelines either as adjuvant radiotherapy (RT) or stereotactic radiosurgery (SRS). Nevertheless, the treatment recommendations are not supported by prospective comparative trials and systematical, critical evaluation of supportive evidence is lacking. For this systematic review, studies analyzing the effectiveness of adjuvant RT and SRS in grade 3 (gr. 3) meningioma were reviewed. Thirty studies met the inclusion criteria for qualitative synthesis, and 6 studies were assessed in quantitative analysis. In quantitative analysis, the weighted average of hazard ratios for adjuvant RT in univariate analyses of overall survival (OS) was 0.55 (CI: 0.41; 0.69). The median 5-year OS after adjuvant RT in gr. 3 meningiomas was 56.3%, and the median OS ranged from 24 to 80 months for patients treated with adjuvant RT versus 13 to 41.2 months in patients not treated. For SRS, the 3-year progression free survival was 0% in one study and 57% in another. The 2-year OS ranged from 25 to 75% in 2 studies. The quality of evidence was rated as “very low” in 14 studies analyzed, and considerable allocation bias was detected. Treatment toxicity was reported in 47% of the studies. The severity, according to the CTCAE, ranged from grades I–V and 5.3 to 100% of patients experienced complications. Adjuvant RT is usually considered standard of care for WHO grade 3 meningiomas, although supporting evidence was of low quality. Better evidence from registries and prospective trials can improve the evidence base for adjuvant fractionated RT in malignant meningiomas.
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Data availability
The data that support the findings of this study are available upon reasonable request from the corresponding author.
Code availability
No custom code was used in this study.
Abbreviations
- RT:
-
Radiotherapy
- SRS:
-
Stereotactic radiosurgery
- OS:
-
Overall survival
- PFS:
-
Progression free survival
- TCR:
-
Tumor control rate
- DFS:
-
Disease free survival
- DSS:
-
Disease specific survival
- RFS:
-
Recurrence free survival
- TTR:
-
Time to recurrence
- RSR:
-
Relative survival rate
- LRC:
-
Locoregional control
References
Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol 21:1–100. https://doi.org/10.1093/neuonc/noz150
Kleihues P, Burger PC, Scheithauer BW (1993) The new WHO classification of brain tumours. In Proceedings of the Brain Pathology; Brain Pathol. Vol. 3, pp. 255–268.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) WHO Classification of Tumours of the Central Nervous System; 4th ed.; International Agency for Research on Cancer, World Health Organization: Lyon.
Mirian C, Duun-Henriksen AK, Juratli T, Sahm F, Spiegl-Kreinecker S, Peyre M, Biczok A, Tonn JC, Goutagny S, Bertero L et al (2020) Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis. J Neurol Neurosurg Psychiatry 91:378–387. https://doi.org/10.1136/JNNP-2019-322257
Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS, Neidert MC, Wirsching H-G, Mawrin C, Ketter R et al (2020) CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathologica 140:3 2020, 140, 409–413. https://doi.org/10.1007/S00401-020-02188-W.
Cassel CK, Guest JA (2012) Choosing wisely: helping physicians and patients make smart decisions about their care. JAMA 307:1801–1802. https://doi.org/10.1001/JAMA.2012.476
Champeaux C, Wilson E, Brandner S, Shieff C, Thorne L (2015) World Health Organization grade III meningiomas A retrospective study for outcome and prognostic factors assessment. Br J Neurosurg 29:693–698. https://doi.org/10.3109/02688697.2015.1054350
Dziuk TW, Woo S, Butler EB, Thornby J, Grossman R, Dennis WS, Lu H, Carpenter LS, Chiu JK (1998) Malignant meningioma: an indication for initial aggressive surgery and adjuvant radiotherapy. J Neurooncol 37:177–188. https://doi.org/10.1023/A:1005853720926
Jääskeläinen J, Haltia M, Servo A (1986) Atypical and anaplastic meningiomas: radiology, surgery, radiotherapy, and outcome. Surg Neurol 25:233–242. https://doi.org/10.1016/0090-3019(86)90233-8
Kumar N, Kumar R, Khosla D, Salunke PS, Gupta SK, Radotra BD (2015) Survival and failure patterns in atypical and anaplastic meningiomas: a single-center experience of surgery and postoperative radiotherapy. J Cancer Res Ther 11:735–739. https://doi.org/10.4103/0973-1482.151426
Rogers L, Barani I, Chamberlain M, Kaley TJ, McDermott M, Raizer J, Schiff D, Weber DC, Wen PY, Vogelbaum MA (2015) Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg 122:4–23
Stessin AM, Schwartz A, Judanin G, Pannullo SC, Boockvar JA, Schwartz TH, Stieg PE, Gabriella Wernicke A (2012) Does adjuvant external-beam radiotherapy improve outcomes for nonbenign meningiomas? A Surveillance, Epidemiology, and End Results (SEER)-based analysis. J Neurosurg 117:669–675. https://doi.org/10.3171/2012.7.JNS111439
Zhang GJ, Zhang YS, Zhang G bin, Li D, Zhang LW, Wu Z, Zhang JT (2018) Prognostic factors and the management of anaplastic meningioma. Clin Neurol Neurosurg, 170, 13–19. https://doi.org/10.1016/j.clineuro.2018.03.028.
Moher D, Liberati A, Tetzlaff J, Altman DG (n.d.) Guidelines and guidance preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. https://doi.org/10.1371/journal.pmed.1000097
Broek JL, Akl EA, Alonso-Coello P, Lang D, Jaeschke R, Williams JW, Phillips B, Lelgemann M, Lethaby A, Bousquet J et al (2009) Grading quality of evidence and strength of recommendations in clinical practice guidelines: part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy: European Journal of Allergy and Clinical Immunology 64, 669–677. https://doi.org/10.1111/J.1398-9995.2009.01973.X.
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P, Debeer H et al (2011) GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64:383–394. https://doi.org/10.1016/j.jclinepi.2010.04.026
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
Alhourani A, Aljuboori Z, Yusuf M, Woo SY, Hattab EM, Andaluz N, Williams BJ (2019) Management trends for anaplastic meningioma with adjuvant radiotherapy and predictors of long-term survival. Neurosurg Focus 46:E4. https://doi.org/10.3171/2019.3.FOCUS1960
Champeaux C, Jecko V (2016) World Health Organization grade III meningiomas. A retrospective study for outcome and prognostic factors assessment. Neurochirurgie 62:203–208. https://doi.org/10.1016/j.neuchi.2016.05.001
Champeaux C, Jecko V, Houston D, Thorne L, Dunn L, Fersht N, Khan AA, Resche-Rigon M (2018) Malignant meningioma: an international multicentre retrospective study. Clin Neurosurg 85:E461–E468. https://doi.org/10.1093/neuros/nyy610
Rosenberg LA, Prayson RA, Lee J, Reddy C, Chao ST, Barnett GH, Vogelbaum MA, Suh JH (2009) Long-term experience with World Health Organization grade III (malignant) meningiomas at a single institution. Int J Radiat Oncol Biol Phys 74:427–432. https://doi.org/10.1016/j.ijrobp.2008.08.018
Sughrue ME, Sanai N, Shangari G, Parsa AT, Berger MS, McDermott MW (2010) Outcome and survival following primary and repeat surgery for World Health Organization grade III meningiomas: clinical article. J Neurosurg 113:202–209. https://doi.org/10.3171/2010.1.JNS091114
Sumner WA, Amini A, Hankinson TC, Foreman NK, Gaspar LE, Kavanagh BD, Karam SD, Rusthoven CG, Liu AK (2017) Survival benefit of postoperative radiation in papillary meningioma: analysis of the National Cancer Data Base. Reports of Practical Oncology and Radiotherapy 22:495–501. https://doi.org/10.1016/j.rpor.2017.10.001
Zhou H, Bai HX, Chan L, Zhang PJ, Karakousis G, Huang R, Xiao B, Yang L (2019) Survival benefit of adjuvant radiotherapy in elderly patients with WHO grade III meningioma. World Neurosurgery 131:e303–e311. https://doi.org/10.1016/j.wneu.2019.07.140
Zhu H, Xie Q, Zhou Y, Chen H, Mao Y, Zhong P, Zheng K, Wang Y, Wang Y, Xie L et al (2015) Analysis of prognostic factors and treatment of anaplastic meningioma in China. J Clin Neurosci 22:690–695. https://doi.org/10.1016/j.jocn.2014.10.023
Ojemann SG, Sneed PK, Larson DA, Gutin PH, Berger MS, Verhey L, Smith V, Petti P, Wara W, Park E, et al (2000) Radiosurgery for malignant meningioma: results in 22 patients. In Proceedings of the Journal of Neurosurgery; American Association of Neurological Surgeons, Vol. 93, pp. 62–67.
Zhang GJ, Zhang G bin, Zhang YS, Li H, Li CB, Zhang LW, Li D, Wu Z, Zhang JT (2018) World Health Organization grade III (nonanaplastic) meningioma: experience in a series of 23 cases. World Neurosurgery, 112, e754–e762. https://doi.org/10.1016/j.wneu.2018.01.149.
Adeberg S, Hartmann C, Welzel T, Rieken S, Habermehl D, von Deimling A, Debus J, Combs SE (2012) Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas - clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy. Int J Radiat Oncol Biol Phys 83:859–864. https://doi.org/10.1016/j.ijrobp.2011.08.010
Coke CC, Corn BW, Werner-Wasik M, Xie Y, Curran WJ (1998) Atypical and malignant meningiomas: an outcome report of seventeen cases. J Neurooncol 39:65–70. https://doi.org/10.1023/A:1005981731739
Detti B, Scoccianti S, di Cataldo V, Monteleone E, Cipressi S, Bordi L, Pellicanò G, Gadda D, Saieva C, Greto D et al (2013) Atypical and malignant meningioma: outcome and prognostic factors in 68 irradiated patients. J Neurooncol 115:421–427. https://doi.org/10.1007/s11060-013-1239-7
Durand A, Labrousse F, Jouvet A, Bauchet L, Kalamaridès M, Menei P, Deruty R, Moreau JJ, Fèvre-Montange M, Guyotat J (2009) WHO grade II and III meningiomas: a study of prognostic factors. J Neurooncol 95:367–375. https://doi.org/10.1007/s11060-009-9934-0
Hug EB, DeVries A, Thornton AF, Munzenrider JE, Pardo FS, Hedley-Whyte ET, Bussiere MR, Ojemann R (2000) Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 48:151–160. https://doi.org/10.1023/A:1006434124794
Pasquier D, Bijmolt S, Veninga T, Rezvoy N, Villa S, Krengli M, Weber DC, Baumert BG, Canyilmaz E, Yalman D et al (2008) Atypical and malignant meningioma: outcome and prognostic factors in 119 irradiated patients A multicenter, retrospective study of the rare cancer network. Int J Radiat Oncol Biol Phys 71:1388–1393. https://doi.org/10.1016/j.ijrobp.2007.12.020
Rogers CL, Won M, Vogelbaum MA, Perry A, Ashby LS, Modi JM, Alleman AM, Galvin J, Fogh SE, Youssef E et al (2020) High-risk meningioma: initial outcomes from NRG oncology/RTOG 0539. Int J Radiat Oncol Biol Phys 106:790–799. https://doi.org/10.1016/j.ijrobp.2019.11.028
Zhao P, Hu M, Zhao M, Ren X, Jiang Z (2014) Prognostic factors for patients with atypical or malignant meningiomas treated at a single center. Neurosurg Rev 38:101–107. https://doi.org/10.1007/s10143-014-0558-2
El-Khatib M, Majdoub F el; Hoevels M, Kocher M, Müller RP, Steiger HJ, Sturm V, Maarouf M (2011) Stereotactic LINAC radiosurgery for incompletely resected or recurrent atypical and anaplastic meningiomas. Acta Neurochirurgica, 153, 1761–1767. https://doi.org/10.1007/s00701-011-1073-7
Ferraro DJ, Funk RK, William Blackett J, Ju MR, DeWees TA, Chicoine MR, Dowling JL, Rich KM, Drzymala RE, Zoberi I, et al (2014) A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas; 2014
Mattozo CA, de Salles AAF, Klement IA, Gorgulho A, McArthur D, Ford JM, Agazaryan N, Kelly DF, Selch MT (2007) Stereotactic radiation treatment for recurrent nonbenign meningiomas. J Neurosurg 106:846–854. https://doi.org/10.3171/jns.2007.106.5.846
Palma L, Celli P, Franco C, Cervoni L, Cantore G (1997) Long-term prognosis for atypical and malignant meningiomas: a study of 71 surgical cases. J Neurosurg 86:793–800. https://doi.org/10.3171/jns.1997.86.5.0793
Pollock BE, Stafford SL, Link MJ, Garces YI, Foote RL (2012) Stereotactic radiosurgery of World Health Organization grade II and III intracranial meningiomas: treatment results on the basis of a 22-year experience. Cancer 118:1048–1054. https://doi.org/10.1002/cncr.26362
Zhang M, Ho AL, D’Astous M, Pendharkar Av, Choi CYH, Thompson PA, Tayag AT, Soltys SG, Gibbs IC, Chang SD (2016) CyberKnife stereotactic radiosurgery for atypical and malignant meningiomas. World Neurosurgery, 91, 574–581.e1. https://doi.org/10.1016/j.wneu.2016.04.019.
Russel DS, Rubinstein LJ (1977) Pathology of tumors of the nervous system; 4th ed.; Edward Arnold: London.
U.S. Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed June 21
Dansk Neuro-Onkologisk Gruppe Kliniske Retningslinjer for Meningeomer 2019 Available online: http://www.dnog.dk/assets/files/Retningslinier_PDF/DNOG_Meningeom_v1.1_AdmGodk181219.pdf. Accessed June 21
Sun SQ, Hawasli AH, Huang J, Chicoine MR, Kim AH (2015) An evidence-based treatment algorithm for the management of WHO grade II and III meningiomas. Neurosurg Focus 38:E3. https://doi.org/10.3171/2015.1.FOCUS14757
Kondziolka D, Flickinger JC, Perez B (1998) Judicious resection and/or radiosurgery for parasagittal meningiomas: outcomes from a multicenter review. Neurosurgery 43:405–413. https://doi.org/10.1097/00006123-199809000-00001
Lippitz BE, Bartek J Jr, Mathiesen T, Förander P (2020) Ten-year follow-up after gamma knife radiosurgery of meningioma and review of the literature. Acta Neurochir 162:2183–2196. https://doi.org/10.1007/S00701-020-04350-5
Lunsford LD (1994) Contemporary management of meningiomas: radiation therapy as an adjuvant and radiosurgery as an alternative to surgical removal? J Neurosurg 80:187–190
Pollock BE, Stafford SL, Utter A, Giannini C, Schreiner SA (2003) Stereotactic radiosurgery provides equivalent tumor control to Simpson grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys 55:1000–1005. https://doi.org/10.1016/S0360-3016(02)04356-0
Mathiesen T, Kihlström L, Svensson M, Bagger-Sjöbäck D (2007) Effects of using combined transpetrosal surgical approaches to treat petroclival meningiomas, 60. https://doi.org/10.1227/01.NEU.0000255476.06247.F1
Mathiesen T, Pettersson-Segerlind J, Kihlströ L, Ulfarsson E (2014) Meningiomas engaging major venous sinuses. World Neurosurgery 81:116–124. https://doi.org/10.1016/j.wneu.2013.01.095
Brett Hauber A, Fairchild AO, Reed Johnson F (2013) Quantifying benefit-risk preferences for medical interventions: an overview of a growing empirical literature. Appl Health Econ Health Policy 11:319–329
Reaney M, Bush E, New M, Paty J, Roborel de Climens A, Skovlund SE, Nelsen L, Flood E, Gater A (2019) The potential role of individual-level benefit-risk assessment in treatment decision making: a DIA study endpoints community workstream. Ther Innov Regul Sci 53, 630–638. https://doi.org/10.1177/2168479018807448.
Bolmsjö IA, Nilstun T, LöFmark R (2007) From cure to palliation: agreement, timing, and decision making within the staff: http://dx.doi.org.ep.fjernadgang.kb.dk/, https://doi.org/10.1177/1049909107300213, 24,366–370. https://doi.org/10.1177/104990910730021
Löfmark R, Nilstun T, Bolmsjö IÅ (2007) From cure to palliation: concept, decision and acceptance. J Med Ethics 33:685–688. https://doi.org/10.1136/JME.2006.018895
Maier AD, Mathiesen T (2022) Granular clinical history and outcome in 51 patients with primary and secondary malignant meningioma. Journal of Neurosurgery - Accepted for publication
Zeng KL, Raman S, Sahgal A, Soliman H, Tsao M, Wendzicki C, Chow E, Lo SS (2017) Patient preference for stereotactic radiosurgery plus or minus whole brain radiotherapy for the treatment of brain metastases. Annals of Palliative Medicine 6:S155–S160. https://doi.org/10.21037/APM.2017.06.11
Braun UK, Beyth RJ, Ford ME, McCullough LB (2007) Defining limits in care of terminally ill patients. BMJ 334:239–241. https://doi.org/10.1136/bmj.39048.475046.68
Birzu C, Peyre M, Sahm F (2020) Molecular alterations in meningioma: prognostic and therapeutic perspectives. Curr Opin Oncol 32:613–622. https://doi.org/10.1097/CCO.0000000000000687
Haslund-Vinding J, Skjoth-Rasmussen J, Poulsgaard L, Fugleholm K, Mirian C, Maier AD, Santarius T, Rom Poulsen F, Meling T, Bartek JJ et al (2021) Proposal of a new grading system for meningioma resection: the Copenhagen Protocol. Acta Neurochir 2021(1):1–10. https://doi.org/10.1007/S00701-021-05025-5
Mirian C, Skyrman S, Bartek J, Jensen LR, Kihlström L, Förander P, Orrego A, Mathiesen T (2020) The Ki-67 proliferation index as a marker of time to recurrence in intracranial meningioma. Neurosurgery 87:1289–1298. https://doi.org/10.1093/NEUROS/NYAA226
Zülch KJ (1979) Histological Typing of Tumours of the Central Nervous System. World Health Organization
Kleihues P, Burger PC, Scheithauer BW (1993) The New WHO Classification of Brain Tumours. Proc Brain Pathol 3:255–268
Kleihues P, Cavenee W (2000) Pathology and Genetics of Tumours of the Nervous System. IARC Press
Louis DN, Ohgaki H, Wiestler OD (2007) WHO Classification of Tumours of the Central Nervous System
Louis DN, Ohgaki H, Wiestler OD (2016) WHO Classification of Tumours of the Central Nervous System. World Health Organization
(2021) WHO Classification of Tumours Editorial Board World Health Organization Classification of Tumours of the Central Nervous System. Word Health Organization
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Amon Bergner, Andrea Daniela Maier, and Tiit Illimar Mathiesen contributed to the study conception and design. Data collection was performed by Amon Bergner and Andrea Daniela Maier. Qualitative and quantitative analyses were performed by Amon Bergner, Andrea Daniela Maier, Tiit Illimar Mathiesen, and Christian Mirian. Quantitative analysis was performed by Amon Bergner, Andrea Daniela Maier, and Christian Mirian. The first draft of the manuscript was written by Amon Bergner, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Unrelated to this work, Christian Mirian is funded by The Novo Nordisk Foundation Grant No. 0052813. Second and last author received a grant from The Danish Cancer Society: R278-A16459. Second author received a grant from The Research Fund of Rigshospitalet, Copenhagen University Hospital. Last author received a grant from the Lundbeck Foundation (R266-2017–4029).
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Bergner, A., Maier, A.D., Mirian, C. et al. Adjuvant radiotherapy and stereotactic radiosurgery in grade 3 meningiomas — a systematic review and meta-analysis. Neurosurg Rev 45, 2639–2658 (2022). https://doi.org/10.1007/s10143-022-01773-9
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DOI: https://doi.org/10.1007/s10143-022-01773-9