Should adjuvant radiotherapy be used in atypical meningioma (WHO grade 2) following gross total resection? A systematic review and Meta-analysis

Figures & data

Figure 1. PRISMA flow diagram.

Table 2. Survival outcomes of GTR alone vs. GTR with adjuvant RT.

	5-year PFS (%)		5-year OS (%)
Study (reference)	GTR alone	GTR + adjuvant RT	GTR alone	GTR + adjuvant RT
Chen et al. 2018 [36]	70	100	90	90
Dohm et al. 2017 [26]	30	48	63	63
Graffeo et al. 2017 [34]	79	88	83	89
Hammouche et al. 2014 [27]	67	100	NR	NR
Jenkinson et al. 2016 [15]	79.3	82	75.7	77
Keric et al. 2020 [28]	68.8	70.7	NR	NR
Lee et al. 2013 [29]	65	74	NR	NR
Park et al. 2013 [33]	70	55	NR	NR
Pant et al. 2018 [30]	35	80	NR	NR
Shakir et al. 2018 [31]	54.1	100	NR	NR
Sun et al. 2014 [32]	86	100	NR	NR
Zhi et al. 2018 [35]	62	84	87	92

GTR: gross total resection. OS: overall survival. PFS: progression free survival. RT: radiation therapy. NR: not reported.

Figure 2. Restricted mean survival of progression free survival.

Figure 3. Hazards ratio of progression free survival.

Figure 4. Restricted mean survival of overall survival.

Figure 5. Hazards ratio of overall survival.

Table 3. Comparison of meta-analysis and systematic reviews on post-operative RT in atypical meningioma.

Study (year)	Inclusion criteria	Statistical method	No. of studies (patients)	WHO grade	GTR alone	GTR + adjuvant RT	LC	PFS	OS	Toxicities	Authors’ conclusion
Hasan et al (2015) [40]	Age > 18, AM/WHO grade 2 meningioma, GTR (Simpson 1–3)	OR X^2test	14 (757)	II	549	208	OR 1.71; 95% CI 0.98–2.98; p = 0.06	NR	OR 0.97; 95% CI 0.39–2.4; p = 0.95	<10%	No significant benefit of post-op RT on survival.
Pereira et al. (2018)^a [41]	Age > 18, AM/WHO grade 2 meningioma 2007/2016	OR	17 (1761)	II	NR	573	OR 1.0448; 95% CI 0.8318–1.3125]; p = 0.7062	NR	NR	NR	RT does not significantly decrease the rate of recurrence in patients with AM.
He et al. (2021) [42]	AM/WHO grade 2 meningioma, WHO classification 2000 or after, 5-year prognostic data available	OR Cochrane’s Q test I2 measurement	17 (2008)	II	1492	369	5-year LC OR 2.59; 95% CI 1.40–4.81; p = 0.002	5-year PFS OR 1.99; 95% CI 1.35–2.95; p = 0.001	5-year OS OR 1.07; 95% CI 0.60–1.91; p = 0.828	NR	PORT significantly improves 5-year LC and PFS.
Chun et al. (2021) [50]	Studies with GTR vs. adjuvant RT reporting LC, PFS, OS	HR	30 (2904)	II	2167	737	OR 0.50; 95% CI 0.36–0.68; p < 0.0001	5-year PFS HR 0.66; 95% CI 0.49–0.89; p = 0.0072	5-year OS HR 1.11; 95% CI 0.67–1.64; p = 0.6548	Mostly G1–2 2.1% G3 2.7% G4	Adjuvant RT confers significant benefits for LC and PFS.
Song et al. (2021) [44]	AM GTR, STR, RT	HR	24 (3078)	II	8 studies	16 studies	Reduced recurrence rate in patients with GTR (PFS: HR 0.69; 95% CI 0.52–0.92, p = 0.01	HR 0.73; 95% CI 0.39–1.34; p = 0.31	HR 0.55; 95% CI 0.36–0.85, p = 0.007	G3–4 in 1 study G2–3 in 1 study G2+ in 1 study G1–2 in 1 study	PORT significantly improved PFS and OS in GTR and STR. Subgroup analysis reported that within the GTR group, only Simpson 3 had significant improvement in PFS.
Zoli et al. (2022) [43]	AM GTR (Simpson 1–3), RT,	OR Mantel- Haenszel model	11	II	NR	NR	NR	1-year PFS OR 0.92 3-year PFS OR 0.31 5-year PFS OR 0.35	NR	NR	Possible protective role of PORT against long-term recurrences.
Our study	AM, GTR (Simpson 1–3), RT, PFS +/- OS reported with survival curves	RMST and HR	12 (1078)	II	803	275	NR	Restricted mean PFS 3.9 months p = 0.037 HR 0.78 p = 0.370	Restricted mean OS 1.1 months p = 0.003 HR 0.79 p = 0.310	Late toxicity: radiation necrosis in 4 patients	Significant PFS and OS benefit, albeit modest, hence there may be an option for close surveillance and early salvage for patients.

*Literature review. AM: atypical meningioma.

GTR: gross total resection. HR: hazards ratio. LC: local control. OS: overall survival. OR: odds ratio. PFS: progression free survival. PORT: post-operative radiotherapy. RMST: restricted mean survival time. STR: subtotal resection.

Table 1. Baseline characteristics of included studies.

Study (ref)	No. of patients	Median age (yrs)	Study design	Study period	WHO classification	Simpson grades included as GTR	Sub-analysis of Simpson grade	GTR alone	GTR + adj RT	Median EBRT dose (Gy)
Chen et al. 2018 [36]	182	57	Retro-spective	1993–2014	At surgery	1 to 3	No	104	10	59.4
Dohm et al. 2017 [26]	117	63	Retro-spective	1993–2014	2007	1 to 3	No	37	41	55.7
Graffeo et al. 2017 [34]	69	60 (no RT); 62 (RT)	Retro-spective	1988–2011	2016	^b	No	61	8	54
Hammouche et al. 2014 [27]	79	58^a	Retro-spective	1996–2009	2007	1	Grade 1	25	9	56.2^c
Jenkinson et al. 2016 [15]	133	62	Retro-spective	2001–2010	At diagnosis	1 to 3	No	81	32	60
Keric et al. 2020 [28]	258	60	Retro-spective	2007–2017	2007	1 to 2	No	168	26	56.6^c
Lee et al. 2013 [29]	90	56.9^a	Retro-spective	1999–2009	2007	1 to 3	No	54	17	59.4
Park et al. 2013 [33]	83	52	Retro-spective	1997–2011	2000/2007	1 to 2	No	38	17	61.2
Pant et al. 2018 [30]	86	51	Retro-spective	2007–2014	2007	1 to 3	No	23	38	59.4
Shakir et al. 2018 [31]	70	62	Retro-spective	1992–2013	2007	1 to 3	No	28	12	54
Sun et al. 2014 [32]	151	54^a	Retro-spective	1993–2012	2007	1 to 3	No	112	39	53.8
Zhi et al. 2018 [35]	149	64	Retro-spective	2000–2012	At diagnosis	1 to 3	No	72	26	59.4

^amean age; ^bGTR defined as absence of nodular enhancement at first post-operative MRI; ^cmean EBRT dose.

EBRT: external beam radiotherapy. GTR: gross total resection. NR: not reported.

Chen WC, Magill ST, Wu A, et al. Histopathological features predictive of local control of atypical meningioma after surgery and adjuvant radiotherapy. J Neurosurg. 2019;130(2):443–450.

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Dohm A, McTyre ER, Chan MD, et al. Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control. J Clin Neurosci. 2017;46:90–98.

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Graffeo CS, Leeper HE, Perry A, et al. Revisiting adjuvant radiotherapy after gross total resection of world health organization grade II meningioma. World Neurosurg. 2017;103:655–663.

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Hammouche S, Clark S, Wong AH, et al. Long-term survival analysis of atypical meningiomas: survival rates, prognostic factors, operative and radiotherapy treatment. Acta Neurochir (Wien). 2014;156(8):1475–1481.

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Jenkinson MD, Waqar M, Farah JO, et al. Early adjuvant radiotherapy in the treatment of atypical meningioma. J Clin Neurosci. 2016;28:87–92.

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Keric N, Kalasauskas D, Freyschlag CF, et al. Impact of postoperative radiotherapy on recurrence of primary intracranial atypical meningiomas. J Neurooncol. 2020;146(2):347–355.

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Lee KD, DePowell JJ, Air EL, et al. Atypical meningiomas: is postoperative radiotherapy indicated? Neurosurg Focus. 2013;35(6):E15.

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Park HJ, Kang HC, Kim IH, et al. The role of adjuvant radiotherapy in atypical meningioma. J Neurooncol. 2013;115(2):241–247.

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Pant S, Tonse R, Kannan S, et al. Impact of timing of radiation therapy on outcomes in atypical meningioma: a clinical audit. Pract Radiat Oncol. 2018;8(5):e275–e284.

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Shakir SI, Souhami L, Petrecca K, et al. Prognostic factors for progression in atypical meningioma. J Neurosurg. 2018;129(5):1240–1248.

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Sun SQ, Kim AH, Cai C, et al. Management of atypical cranial meningiomas, part 1: predictors of recurrence and the role of adjuvant radiation after gross total resection. Neurosurgery. 2014;75(4):347–354. discussion 54-5; quiz 55.

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Zhi M, Girvigian MR, Miller MJ, et al. Long-Term outcomes of newly diagnosed resected atypical meningiomas and the role of adjuvant radiotherapy. World Neurosurg. 2019;122:e1153–e1161.

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Hasan S, Young M, Albert T, et al. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. World Neurosurg. 2015;83(5):808–815.

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Pereira BJA, de Almeida AN, Paiva WS, et al. Impact of radiotherapy in atypical meningioma recurrence: literature review. Neurosurg Rev. 2019;42(3):631–637.

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Data availability statement

The data that support the findings of this study are available online from their respective journal website (please refer to Table 1 for a list of all the included studies and their references).

Table 1. Baseline characteristics of included studies.

Study (ref)	No. of patients	Median age (yrs)	Study design	Study period	WHO classification	Simpson grades included as GTR	Sub-analysis of Simpson grade	GTR alone	GTR + adj RT	Median EBRT dose (Gy)
Chen et al. 2018 [36]	182	57	Retro-spective	1993–2014	At surgery	1 to 3	No	104	10	59.4
Dohm et al. 2017 [26]	117	63	Retro-spective	1993–2014	2007	1 to 3	No	37	41	55.7
Graffeo et al. 2017 [34]	69	60 (no RT); 62 (RT)	Retro-spective	1988–2011	2016	^b	No	61	8	54
Hammouche et al. 2014 [27]	79	58^a	Retro-spective	1996–2009	2007	1	Grade 1	25	9	56.2^c
Jenkinson et al. 2016 [15]	133	62	Retro-spective	2001–2010	At diagnosis	1 to 3	No	81	32	60
Keric et al. 2020 [28]	258	60	Retro-spective	2007–2017	2007	1 to 2	No	168	26	56.6^c
Lee et al. 2013 [29]	90	56.9^a	Retro-spective	1999–2009	2007	1 to 3	No	54	17	59.4
Park et al. 2013 [33]	83	52	Retro-spective	1997–2011	2000/2007	1 to 2	No	38	17	61.2
Pant et al. 2018 [30]	86	51	Retro-spective	2007–2014	2007	1 to 3	No	23	38	59.4
Shakir et al. 2018 [31]	70	62	Retro-spective	1992–2013	2007	1 to 3	No	28	12	54
Sun et al. 2014 [32]	151	54^a	Retro-spective	1993–2012	2007	1 to 3	No	112	39	53.8
Zhi et al. 2018 [35]	149	64	Retro-spective	2000–2012	At diagnosis	1 to 3	No	72	26	59.4

^amean age; ^bGTR defined as absence of nodular enhancement at first post-operative MRI; ^cmean EBRT dose.

EBRT: external beam radiotherapy. GTR: gross total resection. NR: not reported.