Determining the Role of Adjuvant Radiotherapy in the Management of Meningioma

A Surveillance, Epidemiology, and End Results Analysis

Abhinav K. Reddy, MS; James S. Ryoo, BS; Steven Denyer, MS; Laura S. McGuire; Ankit I. Mehta, MD

Neurosurg Focus. 2019;46(6):e3

Abstract and Introduction

Abstract

Objective: The aim of this study was to illustrate the demographic characteristics of meningioma patients and observe the effect of adjuvant radiation therapy on survival by using the Surveillance, Epidemiology, and End Results (SEER) database. More specifically, the authors aimed to answer the question of whether adjuvant radiotherapy following resection of atypical meningioma confers a cause-specific survival benefit. Additionally, they attempted to add to previous characterizations of the epidemiology of primary meningiomas and assess the effectiveness of the standard of care for benign and anaplastic meningiomas. They also sought to characterize the efficacy of various treatment options in atypical and anaplastic meningiomas separately since nearly all other analyses have grouped these two together despite varying treatment regimens for these behavior categories.

Methods: SEER data from 1973 to 2015 were queried using appropriate ICD-O-3 codes for benign, atypical, and anaplastic meningiomas. Patient demographics, tumor characteristics, and treatment choices were analyzed. The effects of treatment were examined using a multivariate Cox proportional hazards model and Kaplan-Meier survival analysis.

Results: A total of 57,998 patients were included in the analysis of demographic, meningioma, and treatment characteristics. Among this population, cases of unspecified WHO tumor grade were excluded in the multivariate analysis, leaving a total of 12,931 patients to examine outcomes among treatment paradigms. In benign meningiomas, gross-total resection (HR 0.289, p = 0.013) imparted a significant cause-specific survival benefit over no treatment. In anaplastic meningioma cases, adjuvant radiotherapy imparted a significant survival benefit following both subtotal (HR 0.089, p = 0.018) and gross-total (HR 0.162, p = 0.002) resection as compared to gross-total resection alone. In atypical tumors, gross-total resection plus radiotherapy did not significantly change the hazard risk (HR 1.353, p = 0.628) compared to gross-total resection alone. Similarly, it was found that adjuvant radiation did not significantly benefit survival after a subtotal resection (HR 1.440, p = 0.644).

Conclusions: The results of this study demonstrate that the role of adjuvant radiotherapy, especially after the resection of atypical meningioma, remains somewhat unclear. Thus, given these results, prospective randomized clinical studies are warranted to provide clear information on the effects of adjuvant radiation in meningioma treatment.

Introduction

MENINGIOMAS are one of the most prevalent forms of tumor seen in the central nervous system (CNS), accounting for about a third of all primary brain and CNS tumors.^[15] They typically arise from arachnoid cap cells in the meninges surrounding the brain and spine, can be readily diagnosed with imaging, and are often found incidentally during imaging for other medical purposes.^[21] An increase in cranial imaging for a variety of medical indications has led to a greater reported incidence of primary meningioma in patients who were not originally being assessed for meningioma.^[18] The majority of meningiomas are benign, slow-growing tumors (ICD-O-3 behavior 0); however, some forms are more aggressive and are categorized as either atypical (ICD-O-3 behavior 1) or anaplastic (ICD-O-3 behavior 3) meningiomas.^[1]

Previous epidemiological studies have shown that benign meningiomas represent approximately 94% of all meningioma cases, whereas atypical and anaplastic meningiomas account for about 4% and 1%, respectively.^[1] These tumors are most common in older individuals, with an average age of approximately 64 years at onset and an increasing incidence with age.^[1] There is also a well-documented increased incidence of these tumors in women (73% in women overall^[8] and 80% of spinal cord meningiomas in women^[23]). Some evidence suggests that this trend is not seen in pediatric patients,^[8] in whom these tumor types are rare and likely associated with neurofibromatosis type 2 (NF2) or therapeutic radiation for other malignancies.^[11] Overall, death from benign meningiomas is very low with exceptions for tumors in locations such as the skull base where the risk from tumor growth is greater.^[5] Atypical and anaplastic meningiomas have lower survival rates and are often associated with recurrence.^[10]

Given that benign meningiomas are a slow-growing malignancy, the usual treatment course involves observation after diagnosis through imaging.^[24] For most patients, the meningioma will be asymptomatic, and as long as the tumor size does not drastically increase, there is no urgency to treat surgically.^[4] However, an exception to this stance relates to pediatric patients, in whom there is the concern that future surgery will be required and the decision to perform gross-total resection (GTR) early may be made.^[14] For most benign meningiomas for which GTR is successfully completed, adjuvant radiotherapy is not indicated.^[5] For atypical meningiomas, which have a higher rate of recurrence, standard practice is to perform GTR when possible; however, there is ongoing debate over whether adjuvant radiotherapy should be provided in cases in which GTR is successful, with studies showing various effects on survival.^[2,3,19] The advent of newer, more focused radiotherapy options has added to the question of whether to radiate in these cases and whether that radiation will improve outcomes. For anaplastic meningiomas, which are highly aggressive and come with a poor prognosis, GTR and subsequent radiotherapy are both indicated.^[16]

In the present study, in which we conducted the largest-to-date Surveillance, Epidemiology, and End Results (SEER) analysis of primary meningiomas, we aimed to answer the question of whether adjuvant radiotherapy following resection of atypical meningioma confers a cause-specific survival benefit. Additionally, we attempted to add to previous characterizations of the epidemiology of primary meningiomas and assess the effectiveness of the standard of care for benign and anaplastic meningiomas. We also sought to characterize the efficacy of various treatment options in atypical and anaplastic meningiomas separately since nearly all other analyses have grouped these two together despite varying treatment regimens for these behavior categories.

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Demographic, tumor, and treatment characteristics of sampled individuals with benign meningioma, grouped according to histological classification
	Total		Meningioma, NOS		Meningothelial Meningioma		Fibrous Meningioma		Psammomatous Meningioma		Angiomatous Meningioma		Transitional Meningioma
Variable	No.	%	No.	%	No.	%	No.	%	No.	%	No.	%	No.	%
Total	55,391	100	47,489	100	3,619	100	1,104	100	1,154	100	354	100	1,671	100
Age group (yrs)
0–19	201	0.4	147	0.3	24	0.7	7	0.6	4	0.4	8	2.3	11	0.7
20–39	3,873	7.0	3,036	6.4	419	11.6	133	12.1	69	6.0	39	11.0	177	10.6
40–59	18,821	34.0	15,272	32.2	1,651	45.6	527	47.7	442	38.3	150	42.4	779	46.6
60–79	22,314	40.3	19,293	40.6	1,338	37.0	382	34.6	531	46.0	145	41.0	625	37.4
80+	10,182	18.4	9,741	20.5	187	5.2	55	5.0	108	9.4	12	3.4	79	4.7
Race
Black	6,809	12.3	5,925	12.5	494	13.7	119	10.8	95	8.2	31	8.8	145	8.7
Other*	4,800	8.7	4,122	8.7	310	8.6	87	7.9	101	8.8	35	9.9	145	8.7
Unknown	741	1.3	643	1.4	44	1.2	8	0.7	14	1.2	4	1.1	28	1.7
White	43,041	77.7	36,799	77.5	2,771	76.6	890	80.6	944	81.8	284	80.2	1,353	81.0
Sex
Female	42,025	75.9	36,250	76.3	2,503	69.2	873	79.1	1,012	87.7	184	52.0	1,203	72.0
Male	13,366	24.1	11,239	23.7	1,116	30.8	231	20.9	142	12.3	170	48.0	468	28.0
Region
Midwest	5,019	9.1	4,348	9.2	327	9.0	97	8.8	93	8.1	31	8.8	123	7.4
North	7,465	13.5	6,484	13.7	421	11.6	129	11.7	140	12.1	41	11.6	250	15.0
South	13,004	23.5	11,372	24.0	804	22.2	267	24.2	220	19.1	57	16.1	284	17.0
West	29,903	54.0	25,285	53.2	2,067	57.1	611	55.3	701	60.8	225	63.6	1,014	60.7
Marital status
Divorced, separated, or widowed	14,905	26.9	13,355	28.1	686	19.0	225	20.4	283	24.5	51	14.4	305	18.3
Married or domestic partner	27,826	50.2	23,335	49.1	2,054	56.8	630	57.1	629	54.5	200	56.5	978	58.5
Single	8,40	16.0	7,326	15.4	745	20.6	204	18.5	179	15.5	77	21.8	309	18.5
Unknown	3,820	6.9	3,473	7.3	134	3.7	45	4.1	63	5.5	26	7.3	79	4.7
Anatomical location
Cerebral meninges	46,307	83.6	40,138	84.5	2,987	82.5	947	85.8	557	48.3	301	85.0	1,377	82.4
Meninges (NOS)	6,109	11.0	5,357	11.3	353	9.8	110	10.0	93	8.1	34	9.6	162	9.7
Nonmeningeal	550	1.0	400	0.8	59	1.6	20	1.8	29	2.5	12	3.4	30	1.8
Spine meninges	2,425	4.4	1,594	3.4	220	6.1	27	2.4	475	41.2	7	2.0	102	6.1
Tumor size
<20 mm	18,802	33.9	17,882	37.7	356	9.8	121	11.0	263	22.8	17	4.8	163	9.8
20–40 mm	16,721	30.2	14,125	29.7	1,144	31.6	393	35.6	360	31.2	131	37.0	568	34.0
>40 mm	10,230	18.5	7,577	16.0	1,357	37.5	388	35.1	183	15.9	137	38.7	588	35.2
Unknown	9,638	17.4	7,905	16.6	762	21.1	202	18.3	348	30.2	69	19.5	352	21.1
WHO grade
Unknown	40,075	72.3	37,039	78.0	1,379	38.1	482	43.7	477	41.3	134	37.9	564	33.8
I	14,434	26.1	9,782	20.6	2,124	58.7	594	53.8	669	58.0	212	59.9	1,053	63.0
II	855	1.5	647	1.4	112	3.1	28	2.5	8	0.7	8	2.3	52	3.1
III	19	0.0	17	0.0	1	0.0	—	—	—	—	—	—	1	0.1
IV	8	0.0	4	0.0	3	0.1	—	—	—	—	—	—	1	0.1
RT
No	51,261	92.5	43,767	92.2	3,391	93.7	1,058	95.8	1,123	97.3	332	93.8	1,590	95.2
Yes	4,130	7.5	3,722	7.8	228	6.3	46	4.2	31	2.7	22	6.2	81	4.8
No chemotherapy	55,391	100	47,489	100	3,619	100	1,104	100	1,154	100	354	100	1,671	100
Surgery type
None	33,068	59.7	32,696	68.8	161	4.4	44	4	57	4.9	15	4.2	95	5.7
Biopsy	5,536	10	3,702	7.8	872	24.1	256	23.2	258	22.4	89	25.1	359	21.5
STR	2,311	4.2	1,621	3.4	336	9.3	116	10.5	74	6.4	33	9.3	131	7.8
GTR	14,476	26.1	9,470	19.9	2,250	62.2	688	62.3	765	66.3	217	61.3	1,086	65
Treatment sequence
No treatment	30,291	54.7	29,937	63	151	4.2	38	3.4	56	4.9	15	4.2	94	5.6
Biopsy	5,243	9.5	3,488	7.3	822	22.7	248	22.5	253	21.9	84	23.7	348	20.8
STR	1,914	3.5	1,321	2.8	279	7.7	105	9.5	64	5.5	30	8.5	115	6.9
GTR	13,813	24.9	9,021	19	2,139	59.1	667	60.4	750	65	203	57.3	1,033	61.8
RT	2,777	5	2,759	5.8	10	0.3	6	0.5	1	0.1	—	—	1	0.1
RT + biopsy	293	0.5	214	0.5	50	1.4	8	0.7	5	0.4	5	1.4	11	0.7
RT + STR	397	0.7	300	0.6	57	1.6	11	1	10	0.9	3	0.8	16	1
RT + GTR	663	1.2	449	0.9	111	3.1	21	1.9	15	1.3	14	4	53	3.2

RT = radiotherapy.
*American Indian, Alaska Native, Asian/Pacific Islander.

Table 2. Demographic, tumor, and treatment characteristics of sampled individuals with atypical or anaplastic meningioma, grouped according to histological classification
	Atypical/Borderline Meningioma								Anaplastic Meningioma
	Total		Meningiomatosis, NOS		Clear Cell Meningioma		Atypical Meningioma		Total		Meningioma, Malignant		Papillary Meningioma
Variable	No.	%	No.	%	No.	%	No.	%	No.	%	No.	%	No.	%
Total	1,838	100	133	100	173	100	1,532	100	769	100	691	100	78	100
Age group (yrs)
0–19	45	2.5	7	5.3	12	6.9	26	1.7	19	2.5	14	2.0	5	6.4
20–39	252	13.7	14	10.5	35	20.2	203	13.3	100	13.0	80	11.6	20	25.6
40–59	753	41.0	51	38.4	79	45.7	623	40.7	308	40.1	281	40.7	27	34.6
60–79	713	38.8	49	36.8	41	23.7	623	40.7	286	37.2	264	38.2	22	28.2
80+	75	4.1	12	9.0	6	3.5	57	3.7	56	7.3	52	7.5	4	5.1
Race
Black	244	13.3	21	15.8	21	12.1	202	13.2	118	15.3	109	15.8	9	11.5
Other*	209	11.4	14	10.5	15	8.7	180	11.8	80	10.4	68	9.8	12	15.4
Unknown	23	1.3	2	1.5	2	1.2	19	1.2	2	0.3	2	0.3	—	—
White	1,362	74.1	96	72.2	135	78.0	1,131	73.8	569	74.0	512	74.1	57	73.1
Sex
Female	1,086	59.1	99	74.4	103	59.5	884	57.7	461	60.0	432	62.5	29	37.2
Male	752	40.9	34	25.6	70	40.5	648	42.3	308	40.1	259	37.5	49	62.8
Region
Midwest	212	11.5	24	18.1	12	6.9	176	11.5	70	9.1	61	8.8	9	11.5
North	253	13.8	19	14.3	22	12.7	212	13.8	180	23.4	168	24.3	12	15.4
South	405	22.0	37	27.8	42	24.3	326	21.3	151	19.6	135	19.5	16	20.5
West	968	52.7	53	39.9	97	56.1	818	53.4	368	47.9	327	47.3	41	52.6
Marital status
Divorced, separated, or widowed	294	16.0	25	18.8	25	14.5	244	15.9	141	18.3	127	18.4	14	18.0
Married or domestic partner	1,039	56.5	68	51.1	88	50.9	883	57.6	414	53.8	373	54.0	41	52.6
Single	411	22.4	28	21.1	51	29.5	332	21.7	173	22.5	152	22.0	21	26.9
Unknown	94	5.1	12	9.0	9	5.2	73	4.8	41	5.3	39	5.6	2	2.6
Anatomical location
Cerebral meninges	1,615	87.9	112	84.2	137	79.2	1,366	89.2	602	78.3	535	77.4	67	85.9
Meninges (NOS)	151	8.2	12	9	12	6.9	127	8.3	105	13.7	99	14.3	6	7.7
Nonmeningeal	22	1.2	6	4.5	.	.	16	1	39	5.1	35	5.1	4	5.1
Spine meninges	50	2.7	3	2.3	24	13.9	23	1.5	23	3	22	3.2	1	1.3
Tumor size
<20 mm	90	4.9	29	21.8	7	4	54	3.5	30	3.9	30	4.3	—	—
20–40 mm	415	22.6	34	25.6	44	25.4	337	22	110	14.3	100	14.5	10	12.8
>40 mm	1,020	55.5	41	30.8	88	50.9	891	58.2	221	28.7	179	25.9	42	53.8
Unknown	313	17	29	21.8	34	19.7	250	16.3	408	53.1	382	55.3	26	33.3
WHO grade
Unknown	427	23.2	94	70.7	33	19.1	300	19.6	472	61.4	447	64.7	25	32.1
I	73	4	21	15.8	6	3.5	46	3	85	11.1	82	11.9	3	3.8
II	1,324	72	18	13.5	131	75.7	1,175	76.7	62	8.1	49	7.1	13	16.7
III	14	0.8	—	—	3	1.7	11	0.7	145	18.9	108	15.6	37	47.4
IV	—	—	—	—	—	—	—	—	5	0.7	5	0.7	—	—
RT
No	1,303	70.9	111	83.5	111	64.2	1,081	70.6	502	65.3	462	66.9	40	51.3
Yes	535	29.1	22	16.5	62	35.8	451	29.4	267	34.7	229	33.1	38	48.7
No chemotherapy	1,838	100	133	100	173	100	1,532	100	769	100	691	100	78	100
Surgery type
None	194	10.6	73	54.9	9	5.2	112	7.3	161	20.9	156	22.6	5	6.4
Biopsy	87	4.7	2	1.5	10	5.8	75	4.9	115	15	106	15.3	9	11.5
STR	295	16.1	10	7.5	35	20.2	250	16.3	84	10.9	66	9.6	18	23.1
GTR	1,262	68.7	48	36.1	119	68.8	1,095	71.5	409	53.2	363	52.5	46	59
Treatment sequence
No treatment	173	9.4	58	43.6	7	4	108	7	127	16.5	122	17.7	5	6.4
Biopsy	—	—	—	—	—	—	—	—	76	9.9	75	10.9	1	1.3
STR	174	9.5	10	7.5	18	10.4	146	9.5	41	5.3	31	4.5	10	12.8
GTR	956	52	43	32.3	86	49.7	827	54	258	33.6	234	33.9	24	30.8
RT	21	1.1	15	11.3	2	1.2	4	0.3	34	4.4	34	4.9	—	—
RT + biopsy	87	4.7	2	1.5	10	5.8	75	4.9	39	5.1	31	4.5	8	10.3
RT + STR	121	6.6	—	—	17	9.8	104	6.8	43	5.6	35	5.1	8	10.3
RT + GTR	306	16.6	5	3.8	33	19.1	268	17.5	151	19.6	129	18.7	22	28.2

*American Indian, Alaska Native, Asian/Pacific Islander.

Table 3. Results of Cox proportional hazards models for benign meningioma
Variable	p Value	HR	95% CI
Treatment sequence
No treatment	Reference
Biopsy	0.0621	0.357	0.121–1.053
STR	0.2992	0.521	0.152–1.785
GTR	0.0129*	0.289	0.109–0.769
RT	0.5435	1.79	0.274–11.702
RT + biopsy	0.3826	0.253	0.012–5.529
RT + STR	0.6517	1.395	0.329–5.917
RT + GTR	0.5371	0.608	0.125–2.956
Histology
Meningioma, NOS	Reference
Meningothelial meningioma	0.5486	1.277	0.574–2.843
Fibrous meningioma	0.7147	0.726	0.131–4.039
Psammomatous meningioma	0.4053	2.046	0.379–11.036
Angiomatous meningioma	0.3551	2.273	0.399–12.95
Transitional meningioma	0.7114	1.248	0.386–4.042
Age (yrs)
0–19	0.635	2.078	0.101–42.6
20–39	0.8374	1.168	0.265–5.14
40–59	Reference
60–79	0.0006*	4.396	1.885–10.249
80+	<0.0001*	19.123	6.941–52.687
Race
White	Reference
Black	0.0112*	2.612	1.244–5.485
Other	0.2635	1.645	0.687–3.937
Sex
Male	Reference
Female	0.0139*	0.462	0.25–0.855
Marital status
Single	Reference
Divorced, separated, or widowed	0.252	0.573	0.221–1.485
Married or domestic partner	0.4601	0.742	0.337–1.637
Anatomical location
Brain meninges	Reference
Meninges (NOS)	0.7866	1.149	0.42–3.141
Nonmeningeal	0.1792	3.081	0.596–15.913
Spine meninges	0.5174	0.38	0.02–7.115
Tumor size
<20 mm	Reference
20–40 mm	0.2387	2.337	0.569–9.598
>40 mm	0.0383*	4.43	1.084–18.114
WHO grade
I	Reference
II	0.0056*	2.963	1.373–6.392

*Statistically significant.

Table 4. Results of Cox proportional hazards models for atypical meningioma
Variable	p Value	HR	95% CI
Treatment sequence
GTR	Reference
No treatment	0.2437	3.107	0.462–20.898
STR	0.0735	2.973	0.902–9.801
RT + biopsy	0.6189	1.600	0.251–10.204
RT + STR	0.0334*	4.282	1.121–16.354
RT + GTR	0.6284	1.353	0.398–4.603
Histology
Atypical meningioma	Reference
Meningiomatosis, NOS	0.3755	0.192	0.005–7.370
Clear cell meningioma	0.3055	0.413	0.076–2.242
Age (yrs)
0–19	0.8308	0.705	0.029–17.373
20–39	0.7527	1.247	0.316–4.914
40–59	Reference
60–79	0.2786	1.784	0.626–5.085
80+	<0.0001*	45.524	11.83–175.178
Race
White	Reference
Black	0.6821	1.269	0.406–3.965
Other	0.5389	0.572	0.096–3.398
Sex
Male	Reference
Female	0.9341	1.035	0.457–2.344
Marital status
Single	Reference
Divorced, separated, or widowed	0.7523	0.817	0.234–2.858
Married or domestic partner	0.2414	0.542	0.195–1.509
Anatomical location
Brain meninges	Reference
Meninges (NOS)	0.8688	0.859	0.141–5.217
Nonmeningeal	0.9959	1.009	0.031–33.056
Spine meninges	0.5941	2.289	0.109–48.141
Tumor size
<20 mm	Reference
20–40 mm	0.5415	0.378	0.017–8.567
>40 mm	0.9252	1.149	0.063–20.945
WHO grade
II	Reference
III	0.0777	5.034	0.836–30.313

*Statistically significant.

Table 5. Results of Cox proportional hazards models for anaplastic meningioma
Variable	p Value	HR	95% CI
Treatment sequence
GTR	Reference
No treatment	0.7305	1.81	0.062–52.894
Biopsy	0.0851	0.144	0.016–1.308
STR	0.2441	0.259	0.027–2.515
RT + biopsy	0.0593	0.261	0.065–1.054
RT + STR	0.0184*	0.089	0.012–0.665
RT + GTR	0.0019*	0.162	0.052–0.511
Histology
Meningioma, malignant	Reference
Papillary meningioma	0.0880	0.273	0.061–1.213
Age (yrs)
0–19	0.3120	6.486	0.173–243.224
20–39	0.7937	0.659	0.029–15.063
40–59	Reference
60–79	0.0113*	4.395	1.399–13.808
80+	0.0640	4.570	0.915–22.822
Race
White	Reference
Black	0.4161	1.650	0.494–5.514
Other	0.9532	1.034	0.337–3.175
Sex
Male	Reference
Female	0.5479	1.295	0.557–3.014
Marital status
Single	Reference
Divorced, separated, or widowed	0.0484*	8.001	1.014–63.108
Married or domestic partner	0.0498*	7.463	1.002–55.603
Anatomical location
Brain meninges	Reference
Meninges (NOS)	0.6773	1.343	0.335–5.38
Nonmeningeal	0.9859	1.033	0.027–39.155
Spine meninges	0.9797	0.957	0.031–29.142
Tumor size
<20 mm	Reference
20–40 mm	0.5001	0.448	0.043–4.629
>40 mm	0.8490	1.213	0.167–8.819
WHO grade
II	Reference
III	0.0050*	8.625	1.914–38.862

*Statistically significant.

Table 6. Treatment sequence results of Cox proportional hazards models for atypical meningioma with STR as the baseline treatment*
Treatment Sequence	p Value	HR	95% CI
STR	Reference
No treatment	0.9671	1.045	0.128–8.562
GTR	0.0735	0.336	0.102–1.109
RT + biopsy	0.5530	0.538	0.070–4.165
RT + STR	0.6438	1.440	0.307–6.766
RT + GTR	0.3012	0.455	0.102–2.024

*All other findings for histology, age, sex, etc. from Table 4 are unchanged in this analysis.

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Determining the Role of Adjuvant Radiotherapy in the Management of Meningioma

A Surveillance, Epidemiology, and End Results Analysis

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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