Determining the role of adjuvant radiotherapy in the management of meningioma: a Surveillance, Epidemiology, and End Results analysis

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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.

ABBREVIATIONS CNS = central nervous system; GTR = gross-total resection; NF2 = neurofibromatosis type 2; NOS = not otherwise specified; SEER = Surveillance, Epidemiology, and End Results; STR = subtotal resection.

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.

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 overall8 and 80% of spinal cord meningiomas in women23). 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.

Methods

Study Sample

A retrospective analysis was performed using the SEER Program database collected by the National Cancer Institute from 1973 to 2015. The data set entitled “Incidence - SEER 18 Regs Custom Data (with additional treatment fields), Nov2017 Sub (1973–2015 varying) - Linked To County Attributes - Total U.S., 1969–2016 Counties” was used, and SEER*STAT version 8.1.2 was used to extract case-level data. SEER contains de-identified individual-level data from 13 cancer registries across the United States.

The ICD-O-3 codes were used to identify 89,525 cases of CNS meningioma for the years 1973–2015. Those cases with data collected from autopsy or death certificate and records with incomplete cause-specific survival data were excluded from our study. ICD-O-3 codes with more than 30 patients and records with only one tumor recorded were included in the study, which resulted in a total of 57,998 cases.

Baseline Characteristics

Analyzed patient demographics included age group (0–19, 20–39, 40–59, 60–79, and 80+ years), sex (female, male), race (black, white, other), and marital status (married/domestic partner, divorced/separated, single, widowed). Studied tumor characteristics included primary tumor site (cerebral meninges C700, spinal meninges C701, meninges not otherwise specified [NOS] C709, brain C710–C719, spinal cord C720, cauda equina C721, olfactory nerve C722, optic nerve C723, acoustic nerve C724, cranial nerve NOS C725, overlapping lesion of brain and CNS C728, nervous system NOS C729, pituitary gland C751, craniopharyngeal duct C752, pineal gland C753) and histology (9530/0: meningioma, NOS; 9531/0: meningothelial meningioma; 9532/0: fibrous meningioma; 9533/0: psammomatous meningioma; 9534/0: angiomatous meningioma; 9537/0: transitional meningioma; 9530/1: meningiomatosis, NOS; 9538/1: clear cell meningioma; 9539/1: atypical meningioma; 9530/3: meningioma, anaplastic; 9533/3: psammomatous meningioma, anaplastic). Treatment characteristics included biopsy, resection (subtotal resection [STR]; GTR, NOS), radiation (yes, no), and chemotherapy (yes, no).

Statistical Analysis

CNS meningiomas were grouped according to behavior category (0, benign; 1, atypical; 3, anaplastic). Patient demographics, tumor characteristics, and treatment regimens for the records identified are summarized in Tables 1 and 2. The effect of treatment regimen on patient survival was evaluated using a Cox proportional hazards model including age, race, sex, marital status, tumor size, histological type, anatomical location, and WHO grade (Tables 36). A Firth bias correction was applied to account for the small sample sizes seen in some subgroups.12 Mortality was defined as cause-specific mortality from a CNS cancer and did not count individuals who died of noncancerous causes, with the follow-up from date of diagnosis until 2015. Additionally, graphic analysis using the Kaplan-Meier method was fitted to evaluate the association between treatment sequence and survival, stratified by anatomical location. Multiple comparisons for the log-rank test with Sidak correction were then performed to compare the different treatment regimens. Multivariate logistic regression models adjusted for sex, age groups, race, marital status, histological type, anatomical location, tumor size, WHO grade, radiation, and surgical intervention were fitted to evaluate the association between treatment sequence and cause-specific survival (Fig. 1). Only variables with more than 80% completion rates were included in the multivariate model. For the survival analyses mentioned above, only samples for which the WHO grade was recorded were included in the analysis. Additionally, since the WHO only recognizes grades I, II, and III as options in the grading of meningiomas, patients with a reported WHO grade IV tumor were removed from all survival analyses. The significance level was set at alpha = 0.05. Odds ratios, hazard ratios, 95% confidence intervals, and p values were calculated. SAS software version 9.4 M3 for Linux was used to perform all data analysis (SAS Institute). This study complies with STROBE guidelines.22

TABLE 1.

Demographic, tumor, and treatment characteristics of sampled individuals with benign meningioma, grouped according to histological classification

TotalMeningioma, NOSMeningothelial MeningiomaFibrous MeningiomaPsammomatous MeningiomaAngiomatous MeningiomaTransitional Meningioma
VariableNo.%No.%No.%No.%No.%No.%No.%
Total55,39110047,4891003,6191001,1041001,1541003541001,671100
Age group (yrs)
 0–192010.41470.3240.770.640.482.3110.7
 20–393,8737.03,0366.441911.613312.1696.03911.017710.6
 40–5918,82134.015,27232.21,65145.652747.744238.315042.477946.6
 60–7922,31440.319,29340.61,33837.038234.653146.014541.062537.4
 80+10,18218.49,74120.51875.2555.01089.4123.4794.7
Race
 Black6,80912.35,92512.549413.711910.8958.2318.81458.7
 Other*4,8008.74,1228.73108.6877.91018.8359.91458.7
 Unknown7411.36431.4441.280.7141.241.1281.7
 White43,04177.736,79977.52,77176.689080.694481.828480.21,35381.0
Sex
 Female42,02575.936,25076.32,50369.287379.11,01287.718452.01,20372.0
 Male13,36624.111,23923.71,11630.823120.914212.317048.046828.0
Region
 Midwest5,0199.14,3489.23279.0978.8938.1318.81237.4
 North7,46513.56,48413.742111.612911.714012.14111.625015.0
 South13,00423.511,37224.080422.226724.222019.15716.128417.0
 West29,90354.025,28553.22,06757.161155.370160.822563.61,01460.7
Marital status
 Divorced, separated, or widowed14,90526.913,35528.168619.022520.428324.55114.430518.3
 Married or domestic partner27,82650.223,33549.12,05456.863057.162954.520056.597858.5
 Single8,4016.07,32615.474520.620418.517915.57721.830918.5
 Unknown3,8206.93,4737.31343.7454.1635.5267.3794.7
Anatomical location
 Cerebral meninges46,30783.640,13884.52,98782.594785.855748.330185.01,37782.4
 Meninges (NOS)6,10911.05,35711.33539.811010.0938.1349.61629.7
 Nonmeningeal5501.04000.8591.6201.8292.5123.4301.8
 Spine meninges2,4254.41,5943.42206.1272.447541.272.01026.1
Tumor size
 <20 mm18,80233.917,88237.73569.812111.026322.8174.81639.8
 20–40 mm16,72130.214,12529.71,14431.639335.636031.213137.056834.0
 >40 mm10,23018.57,57716.01,35737.538835.118315.913738.758835.2
 Unknown9,63817.47,90516.676221.120218.334830.26919.535221.1
WHO grade
 Unknown40,07572.337,03978.01,37938.148243.747741.313437.956433.8
 I14,43426.19,78220.62,12458.759453.866958.021259.91,05363.0
 II8551.56471.41123.1282.580.782.3523.1
 III190.0170.010.010.1
 IV80.040.030.110.1
RT
 No51,26192.543,76792.23,39193.71,05895.81,12397.333293.81,59095.2
 Yes4,1307.53,7227.82286.3464.2312.7226.2814.8
No chemotherapy55,39110047,4891003,6191001,1041001,1541003541001,671100
Surgery type
 None33,06859.732,69668.81614.4444574.9154.2955.7
 Biopsy5,536103,7027.887224.125623.225822.48925.135921.5
 STR2,3114.21,6213.43369.311610.5746.4339.31317.8
 GTR14,47626.19,47019.92,25062.268862.376566.321761.31,08665
Treatment sequence
 No treatment30,29154.729,937631514.2383.4564.9154.2945.6
 Biopsy5,2439.53,4887.382222.724822.525321.98423.734820.8
 STR1,9143.51,3212.82797.71059.5645.5308.51156.9
 GTR13,81324.99,021192,13959.166760.47506520357.31,03361.8
 RT2,77752,7595.8100.360.510.110.1
 RT + biopsy2930.52140.5501.480.750.451.4110.7
 RT + STR3970.73000.6571.6111100.930.8161
 RT + GTR6631.24490.91113.1211.9151.3144533.2

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 MeningiomaAnaplastic Meningioma
TotalMeningiomatosis, NOSClear Cell MeningiomaAtypical MeningiomaTotalMeningioma, MalignantPapillary Meningioma
VariableNo.%No.%No.%No.%No.%No.%No.%
Total1,8381001331001731001,53210076910069110078100
Age group (yrs)
 0–19452.575.3126.9261.7192.5142.056.4
 20–3925213.71410.53520.220313.310013.08011.62025.6
 40–5975341.05138.47945.762340.730840.128140.72734.6
 60–7971338.84936.84123.762340.728637.226438.22228.2
 80+754.1129.063.5573.7567.3527.545.1
Race
 Black24413.32115.82112.120213.211815.310915.8911.5
 Other*20911.41410.5158.718011.88010.4689.81215.4
 Unknown231.321.521.2191.220.320.3
 White1,36274.19672.213578.01,13173.856974.051274.15773.1
Sex
 Female1,08659.19974.410359.588457.746160.043262.52937.2
 Male75240.93425.67040.564842.330840.125937.54962.8
Region
 Midwest21211.52418.1126.917611.5709.1618.8911.5
 North25313.81914.32212.721213.818023.416824.31215.4
 South40522.03727.84224.332621.315119.613519.51620.5
 West96852.75339.99756.181853.436847.932747.34152.6
Marital status
 Divorced, separated, or widowed29416.02518.82514.524415.914118.312718.41418.0
 Married or domestic partner1,03956.56851.18850.988357.641453.837354.04152.6
 Single41122.42821.15129.533221.717322.515222.02126.9
 Unknown945.1129.095.2734.8415.3395.622.6
Anatomical location
 Cerebral meninges1,61587.911284.213779.21,36689.260278.353577.46785.9
 Meninges (NOS)1518.2129126.91278.310513.79914.367.7
 Nonmeningeal221.264.5..161395.1355.145.1
 Spine meninges502.732.32413.9231.5233223.211.3
Tumor size
 <20 mm904.92921.874543.5303.9304.3
 20–40 mm41522.63425.64425.43372211014.310014.51012.8
 >40 mm1,02055.54130.88850.989158.222128.717925.94253.8
 Unknown313172921.83419.725016.340853.138255.32633.3
WHO grade
 Unknown42723.29470.73319.130019.647261.444764.72532.1
 I7342115.863.54638511.18211.933.8
 II1,324721813.513175.71,17576.7628.1497.11316.7
 III140.831.7110.714518.910815.63747.4
 IV50.750.7
RT
 No1,30370.911183.511164.21,08170.650265.346266.94051.3
 Yes53529.12216.56235.845129.426734.722933.13848.7
No chemotherapy1,8381001331001731001,53210076910069110078100
Surgery type
 None19410.67354.995.21127.316120.915622.656.4
 Biopsy874.721.5105.8754.91151510615.3911.5
 STR29516.1107.53520.225016.38410.9669.61823.1
 GTR1,26268.74836.111968.81,09571.540953.236352.54659
Treatment sequence
 No treatment1739.45843.674108712716.512217.756.4
 Biopsy769.97510.911.3
 STR1749.5107.51810.41469.5415.3314.51012.8
 GTR956524332.38649.78275425833.623433.92430.8
 RT211.11511.321.240.3344.4344.9
 RT + biopsy874.721.5105.8754.9395.1314.5810.3
 RT + STR1216.6179.81046.8435.6355.1810.3
 RT + GTR30616.653.83319.126817.515119.612918.72228.2

American Indian, Alaska Native, Asian/Pacific Islander.

TABLE 3.

Results of Cox proportional hazards models for benign meningioma

Variablep ValueHR95% CI
Treatment sequence
 No treatmentReference
 Biopsy0.06210.3570.121–1.053
 STR0.29920.5210.152–1.785
 GTR0.0129*0.2890.109–0.769
 RT0.54351.790.274–11.702
 RT + biopsy0.38260.2530.012–5.529
 RT + STR0.65171.3950.329–5.917
 RT + GTR0.53710.6080.125–2.956
Histology
 Meningioma, NOSReference
 Meningothelial meningioma0.54861.2770.574–2.843
 Fibrous meningioma0.71470.7260.131–4.039
 Psammomatous meningioma0.40532.0460.379–11.036
 Angiomatous meningioma0.35512.2730.399–12.95
 Transitional meningioma0.71141.2480.386–4.042
Age (yrs)
 0–190.6352.0780.101–42.6
 20–390.83741.1680.265–5.14
 40–59Reference
 60–790.0006*4.3961.885–10.249
 80+<0.0001*19.1236.941–52.687
Race
 WhiteReference
 Black0.0112*2.6121.244–5.485
 Other0.26351.6450.687–3.937
Sex
 MaleReference
 Female0.0139*0.4620.25–0.855
Marital status
 SingleReference
 Divorced, separated, or widowed0.2520.5730.221–1.485
 Married or domestic partner0.46010.7420.337–1.637
Anatomical location
 Brain meningesReference
 Meninges (NOS)0.78661.1490.42–3.141
 Nonmeningeal0.17923.0810.596–15.913
 Spine meninges0.51740.380.02–7.115
Tumor size
 <20 mmReference
 20–40 mm0.23872.3370.569–9.598
 >40 mm0.0383*4.431.084–18.114
WHO grade
 IReference
 II0.0056*2.9631.373–6.392

Statistically significant.

TABLE 4.

Results of Cox proportional hazards models for atypical meningioma

Variablep ValueHR95% CI
Treatment sequence
 GTRReference
 No treatment0.24373.1070.462–20.898
 STR0.07352.9730.902–9.801
 RT + biopsy0.61891.6000.251–10.204
 RT + STR0.0334*4.2821.121–16.354
 RT + GTR0.62841.3530.398–4.603
Histology
 Atypical meningiomaReference
 Meningiomatosis, NOS0.37550.1920.005–7.370
 Clear cell meningioma0.30550.4130.076–2.242
Age (yrs)
 0–190.83080.7050.029–17.373
 20–390.75271.2470.316–4.914
 40–59Reference
 60–790.27861.7840.626–5.085
 80+<0.0001*45.52411.83–175.178
Race
 WhiteReference
 Black0.68211.2690.406–3.965
 Other0.53890.5720.096–3.398
Sex
 MaleReference
 Female0.93411.0350.457–2.344
Marital status
 SingleReference
 Divorced, separated, or widowed0.75230.8170.234–2.858
 Married or domestic partner0.24140.5420.195–1.509
Anatomical location
 Brain meningesReference
 Meninges (NOS)0.86880.8590.141–5.217
 Nonmeningeal0.99591.0090.031–33.056
 Spine meninges0.59412.2890.109–48.141
Tumor size
 <20 mmReference
 20–40 mm0.54150.3780.017–8.567
 >40 mm0.92521.1490.063–20.945
WHO grade
 IIReference
 III0.07775.0340.836–30.313

Statistically significant.

TABLE 5.

Results of Cox proportional hazards models for anaplastic meningioma

Variablep ValueHR95% CI
Treatment sequence
 GTRReference
 No treatment0.73051.810.062–52.894
 Biopsy0.08510.1440.016–1.308
 STR0.24410.2590.027–2.515
 RT + biopsy0.05930.2610.065–1.054
 RT + STR0.0184*0.0890.012–0.665
 RT + GTR0.0019*0.1620.052–0.511
Histology
 Meningioma, malignantReference
 Papillary meningioma0.08800.2730.061–1.213
Age (yrs)
 0–190.31206.4860.173–243.224
 20–390.79370.6590.029–15.063
 40–59Reference
 60–790.0113*4.3951.399–13.808
 80+0.06404.5700.915–22.822
Race
 WhiteReference
 Black0.41611.6500.494–5.514
 Other0.95321.0340.337–3.175
Sex
 MaleReference
 Female0.54791.2950.557–3.014
Marital status
 SingleReference
 Divorced, separated, or widowed0.0484*8.0011.014–63.108
 Married or domestic partner0.0498*7.4631.002–55.603
Anatomical location
 Brain meningesReference
 Meninges (NOS)0.67731.3430.335–5.38
 Nonmeningeal0.98591.0330.027–39.155
 Spine meninges0.97970.9570.031–29.142
Tumor size
 <20 mmReference
 20–40 mm0.50010.4480.043–4.629
 >40 mm0.84901.2130.167–8.819
WHO grade
 IIReference
 III0.0050*8.6251.914–38.862

Statistically significant.

TABLE 6.

Treatment sequence results of Cox proportional hazards models for atypical meningioma with STR as the baseline treatment*

Treatment Sequencep ValueHR95% CI
STRReference
No treatment0.96711.0450.128–8.562
GTR0.07350.3360.102–1.109
RT + biopsy0.55300.5380.070–4.165
RT + STR0.64381.4400.307–6.766
RT + GTR0.30120.4550.102–2.024

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

FIG. 1.
FIG. 1.

Kaplan-Meier survival curve assessing cause-specific mortality for patients with atypical meningiomas. No statistically significant differences were noted between treatment groups.

Results

Sample Characteristics

A total of 57,998 patients in the SEER database met the study criteria and were considered for analysis. Patients were further divided according to tumor behavior and histological classification. Analyses of patient and tumor characteristics were performed within each behavioral group and are represented in Tables 1 and 2.

Ninety-six percent of the patients (55,391) were diagnosed with benign meningiomas. Patients in this category were predominantly 60–79 years old at diagnosis (22,314 [40.3%]), female (42,025 [75.9%]), and white (43,041 [77.7%]). Tumors were mostly < 20 mm (18,802 [33.9%]) or 20–40 mm (16,721 [30.2%]) in size and were predominantly located in the cerebral meninges (46,307 [83.6%]). One lesion subtype, psammomatous meningioma, had a greater tendency to be located in the spinal meninges (475 [41.2%]) compared to benign meningiomas in general (2425 [4.4%]).

Atypical meningiomas were found in 1838 (3.2%) patients. They mostly occurred in the patients who were female (1086 [59.1%]), white (1362 [74.1%]), and ages 40–59 years (753 [41.0%]) or 60–79 years (713 [38.8%]). The tumors mostly arose in the cerebral meninges (1615 [87.9%]) and presented with sizes > 40 mm (1020 [55.5%]). However, meningiomatosis (NOS) had a more even distribution among the tumor size categories of < 20 mm (29 [21.8%]), 20–40 mm (34 [25.6%]), and > 40 mm (41 [30.8%]).

Seven hundred sixty-nine (1.3%) cases were identified as anaplastic meningiomas. Much like the other two groups of tumors, the pattern of white (569 [74.0%]), married (414 [53.8%]), female (461 [60.0%]) patients was seen in the anaplastic type. However, the papillary meningioma subtype specifically showed a male predominance (49 [62.8%]). The age group most affected was 40–59 years old (308 [40.1%]), followed by 60–79 years old (286 [37.2%]). Tumors were generally located in the cerebral meninges (602 [78.3%]). Although most cases had tumors measuring > 40 mm in size (221 [28.7%]), a majority of cases in this behavior category had unknown sizes (408 [53.1%]).

Trends in Treatment Paradigms

Tables 1 and 2 outline the trends in the treatment paradigms for each type of meningioma. Of the three behavior categories, benign meningiomas were least likely to be treated (30,291 [54.7%]). When they were treated, however, resection was preferred, with GTR being achieved in 13,813 (24.9%) patients. Generally, no radiotherapy (51,261 [92.5%]) was administered. Cases of atypical meningioma were managed mostly by GTR alone (956 [52.0%]), followed by GTR and radiation (306 [16.6%]). A total of 535 (29.1%) patients did receive radiotherapy. Anaplastic tumors were managed similarly to atypical tumors, with most treated via GTR alone (258 [33.6%]) or GTR followed by radiation (151 [19.6%]). A higher proportion of patients with anaplastic tumors received radiotherapy (267 [34.7%]) compared to the other groups.

Multivariate Results

The outcomes of different treatment sequences were examined using multivariate analysis with the Cox proportional hazards model, controlling for histological characteristics, demographic factors, anatomical location and size of the tumor, and WHO grade. Tumors without a known WHO grade were excluded from this analysis. In the benign meningioma group (11,673 cases; Table 3), GTR, as compared to no treatment, yielded a significant decrease in the cause-specific mortality risk (HR 0.289, 95% CI 0.109–0.769, p = 0.0129). In the analysis of atypical and anaplastic meningiomas, the reference group was set as GTR in order to better examine the effects of radiotherapy on the risk of death since all standard of care in these treatments involved attempts at GTR. In doing this, we observed that for anaplastic tumors (166 cases; Table 5), adjuvant radiation led to a significant decrease in mortality for the patients who had undergone either GTR (HR 0.162, 95% CI 0.052–0.511, p = 0.0019) or STR (HR 0.089, 95% CI 0.012–0.665, p = 0.0184). However, for atypical tumors (1092 cases; Table 4), adjuvant radiation therapy with STR increased the mortality risk compared to GTR alone (HR 4.282, 95% CI 1.121–16.354, p = 0.0334). Moreover, we saw that the addition of adjuvant radiotherapy had no statistically significant effect in patients with GTR (HR 1.353, 95% CI 0.398–4.603, p = 0.6284).

Across all behavior types of meningioma, an increase in mortality risk was seen in the patient populations ages 60–79 and above 80 compared to patients 40–59 years old (HR 4.396, p = 0.0006 and HR 19.123, p < 0.0001 for benign; HR 1.784, p = 0.2786 and HR 45.523, p < 0.0001 for atypical; HR 4.395, p = 0.0113 and HR 4.570, p = 0.0640 for anaplastic). In benign meningiomas, significantly increased mortality was associated with an increased tumor size and WHO grade II tumors (HR 4.430, 95% CI 1.084–18.114, p = 0.0383; HR 2.963, 95% CI 1.373–6.392, p = 0.0056, respectively). A similar trend was seen for anaplastic tumors, in which WHO grade III meningiomas had unfavorable outcomes compared to WHO grade II tumors (HR 8.625, 95% CI 1.914–38.862, p = 0.005).

In order to more closely examine the increased mortality risk associated with both STR and RT in atypical meningiomas, we performed a breakaway analysis comparing all treatment groups, with STR as the reference group (Table 6). We found that adjuvant radiation did not significantly lower risks in the setting of performing STR (HR 1.440, 95% CI 0.307–6.766, p = 0.6438).

Graphic analysis using the Kaplan-Meier curve was performed to evaluate the association between treatment sequences involving resection or radiation and survival outcomes in atypical meningiomas (Fig. 1). Using a log-rank test with Sidak correction, we found no significant differences between any of the four treatment groups tested.

Discussion

This largest-to-date SEER-based assessment of the epidemiology of primary meningiomas included a total of 57,998 patients. Our study confirmed previously reported information suggesting a predisposition for benign meningiomas in older, female, white populations1,5,10 with the tumors predominantly smaller than 40 mm and located in the cerebral meninges.1 Similar distributions of patient demographics were seen in the atypical and anaplastic cases with the only difference in lesion characteristics being a larger proportion of cases with tumors larger than 40 mm, which is consistent with the literature.2

The Cox proportional hazards model allowed us to assess the relative hazard of various treatment paradigms on the cause-specific mortality of patients with various levels of primary meningioma. For benign meningiomas, standard of care is a “wait and watch” approach for most of the nonaggressively growing tumors, performing resection only in those cases in which size may create a mass effect or growth rates increase.4 This is reflected in our analysis, which showed that the majority of patients received no treatment and that even when resection was performed, radiotherapy was uncommon. Our analysis also showed a significantly lower HR for patients who underwent GTR but no significant HRs for the other treatments. This suggests that in patients with symptoms associated with their benign tumors, resection without the use of adjuvant radiotherapy is beneficial, which is consistent with the literature.5

In atypical meningioma, the standard of care is GTR when possible, although there is no consistency regarding the role of radiotherapy.2,3,19 Our analysis showed that more than a quarter of all atypical meningiomas were treated with adjuvant radiotherapy. In cases in which STR was performed with adjuvant radiotherapy, there was a significantly increased hazard as compared to GTR alone. This finding confirms that GTR should always be attempted. However, our data showed that after GTR, radiation did not impart a significant survival benefit despite the trend of using adjuvant radiotherapy for these tumors. Additionally, our findings showed that, compared to a baseline of performing STR only, radiotherapy following STR was not associated with a lower HR. Therefore, even in cases in which surgeons are unable to resect the entirety of an atypical meningioma, our data do not support the use of concomitant radiotherapy.

The standard of care for anaplastic meningioma is to perform GTR if possible and to provide adjuvant radiotherapy.16 Our data revealed that only about a third of all patients received adjuvant radiotherapy despite this standard. Our analysis showed that, compared to GTR alone, patients undergoing both GTR and adjuvant radiotherapy or both STR and adjuvant radiotherapy had significantly lower HRs. Prior retrospective research similarly showed that the use of all available treatment methods in anaplastic populations is associated with an increased 10-year survival.20 This supports the current standard of including adjuvant radiotherapy in the treatment sequence, regardless of the degree of resection, to improve patient outcomes.

Because of the limitations inherent to the SEER database, the results of this analysis should be taken with a degree of caution. Primarily, the lack of NF2 status information for patients in the database precludes one from extrapolating on a known driver of meningioma.17 Without the patient-level NF2 status, there may be a level of stratification of treatment choices for the patients with atypical meningiomas that is not reflected in the cofactors controlled for in the analysis. Additionally, the SEER database is limited in that it does not offer data on the dosing and modality of the radiation provided; therefore, we could not make any inferences about the relative magnitude of radiation therapy received by any one patient population or the overarching trends in the type of radiation therapy given over time. This absent characterization of radiation is an important consideration given that patients who are clinically judged to have a high risk of recurrence may receive a different level or modality of radiation than the general population.7 Additionally, we were unable to assess whether certain types of radiation therapy or dosing regimens were associated with increased rates of survival.

Neither were there any Simpson resection grades in this data set, which would have provided for a more graded evaluation of the level of resection. While this grading scheme is often used by surgeons to predict the probability of recurrence, our analysis was limited to delineating GTR versus STR. These factors impact the susceptibility of recurrence, which is another limitation in using this type of registry data since it is not possible to track the length of progression-free survival or whether a particular patient had a meningioma recurrence. Instead, the metric of cause-specific mortality is the only outcome available. Previous work has shown that radiation may be helpful in preventing further recurrence of meningioma,9 but the evidence is not definitive.6 Although our study showed that the use of radiation in patients with atypical meningiomas may not confer a survival benefit in patients with single tumors, we cannot determine whether radiation prevents recurrent tumors.

One factor that may not provide a clear bias but is worth noting is the large proportion of patients in the SEER database who did not have WHO grading of their tumors. These patients were removed from the survival analysis, and this decision could have introduced confounding if the lack of documentation is associated with prognostic factors. However, it is reasonable to assume that whether a physician noted a WHO grade for a particular patient in the registry is independent of the disease severity. Additionally, it should be acknowledged that using registry databases such as SEER comes with inherent limitations such as bias based on locations in the country that contribute to the database and the potential differences in reporting methodologies at each location. Registry databases may also underreport cases for which there are no clinical symptoms and therefore present with selection bias.13

In the absence of a similarly large-scale database that includes these other factors, this analysis represents the largest available baseline from which to work, with acknowledgment of its limitations, and makes valuable suggestions about the treatment choices that physicians make. Moreover, given the limitations of using this type of registry data, we strongly suggest that further work be done in a prospective manner (while documenting a wide variety of clinically relevant cofactors) to assess the effectiveness of adjuvant radiotherapy use (while noting the specific type and dosing regimen) after resection of an atypical meningioma.

Conclusions

The results of this retrospective population-based study provide some insight into the role of adjuvant radiotherapy in the management of meningiomas. We demonstrated that the use of radiation after an attempt at GTR did not impart a mortality risk reduction in cases of benign or atypical meningiomas. Notably, adjuvant radiation did not significantly reduce the hazard risk in the STR of atypical meningiomas, suggesting that radiotherapy may not be beneficial despite residual tumor. On the other hand, anaplastic meningiomas did see significant risk reduction with radiotherapy following both GTR and STR. Given the inherent limitations of the SEER database and retrospective analysis, our results are insufficient to redefine the standard management of these tumors; however, they do provide a direction for prospective randomized clinical trials to measure the outcomes of radiation therapy after meningioma resection and define which populations may benefit from adjuvant radiotherapy.

Disclosures

Dr. Mehta has been a consultant for DePuy Synthes and Globus Medical.

Author Contributions

Conception and design: Mehta, Reddy, Ryoo, Denyer. Acquisition of data: Mehta. Analysis and interpretation of data: Reddy, Ryoo, Denyer, McGuire. Drafting the article: Reddy, Ryoo, Denyer. Critically revising the article: Ryoo, McGuire. Reviewed submitted version of manuscript: all authors. Statistical analysis: Reddy, Denyer. Study supervision: Mehta.

Supplemental Information

Videos

References

  • 1

    Agarwal VMcCutcheon BAHughes JDCarlson MLGlasgow AEHabermann EB: Trends in management of intracranial meningiomas: analysis of 49,921 cases from modern cohort. World Neurosurg 106:1451512017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Aizer AABi WLKandola MSLee EQNayak LRinne ML: Extent of resection and overall survival for patients with atypical and malignant meningioma. Cancer 121:437643812015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Barthélemy ELoewenstern JKonuthula NPain MHall JGovindaraj S: Primary management of atypical meningioma: treatment patterns and survival outcomes by patient age. J Cancer Res Clin Oncol 144:9699782018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Buerki RAHorbinski CMKruser THorowitz PMJames CDLukas RV: An overview of meningiomas. Future Oncol 14:216121772018

  • 5

    Cahill KSClaus EB: Treatment and survival of patients with nonmalignant intracranial meningioma: results from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Clinical article. J Neurosurg 115:2592672011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Champeaux CHouston DDunn L: Atypical meningioma. A study on recurrence and disease-specific survival. Neurochirurgie 63:2732812017

  • 7

    Chan AWBernstein KDAdams JAParambi RJLoeffler JS: Dose escalation with proton radiation therapy for high-grade meningiomas. Technol Cancer Res Treat 11:6076142012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Dudley RWRTorok MRRandall SBéland BHandler MHMulcahy-Levy JM: Pediatric versus adult meningioma: comparison of epidemiology, treatments, and outcomes using the Surveillance, Epidemiology, and End Results database. J Neurooncol 137:6216292018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Dziuk TWWoo SButler EBThornby JGrossman RDennis WS: Malignant meningioma: an indication for initial aggressive surgery and adjuvant radiotherapy. J Neurooncol 37:1771881998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Garzon-Muvdi TYang WLim MBrem HHuang J: Atypical and anaplastic meningioma: outcomes in a population based study. J Neurooncol 133:3213302017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Grossbach AJMahaney KBMenezes AH: Pediatric meningiomas: 65-year experience at a single institution. J Neurosurg Pediatr 20:42502017

  • 12

    Heinze G: A comparative investigation of methods for logistic regression with separated or nearly separated data. Stat Med 25:421642262006

  • 13

    Karhade AVLarsen AMGCote DJDubois HMSmith TR: National databases for neurosurgical outcomes research: options, strengths, and limitations. Neurosurgery 83:3333442018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Kotecha RSJunckerstorff RCLee SCole CHGottardo NG: Pediatric meningioma: current approaches and future direction. J Neurooncol 104:1102011

  • 15

    Ostrom QTGittleman HFulop JLiu MBlanda RKromer C: CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol 17 (Suppl 4):iv1iv622015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Paldor IAwad MSufaro YZKaye AHShoshan Y: Review of controversies in management of non-benign meningioma. J Clin Neurosci 31:37462016

  • 17

    Rogers LBarani IChamberlain MKaley TJMcDermott MRaizer J: Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg 122:4232015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Solheim OTorsteinsen MJohannesen TBJakola AS: Effects of cerebral magnetic resonance imaging in outpatients on observed incidence of intracranial tumors and patient survival: a national observational study. J Neurosurg 120:8278322014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Stessin AMSchwartz AJudanin GPannullo SCBoockvar JASchwartz TH: Does adjuvant external-beam radiotherapy improve outcomes for nonbenign meningiomas? A Surveillance, Epidemiology, and End Results (SEER)–based analysis. J Neurosurg 117:6696752012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Sughrue MESanai NShangari GParsa ATBerger MSMcDermott MW: Outcome and survival following primary and repeat surgery for World Health Organization Grade III meningiomas. J Neurosurg 113:2022092010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Vernooij MWIkram MATanghe HLVincent AJHofman AKrestin GP: Incidental findings on brain MRI in the general population. N Engl J Med 357:182118282007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    von Elm EAltman DGEgger MPocock SJGøtzsche PCVandenbroucke JP: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61:3443492008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Westwick HJShamji MF: Effects of sex on the incidence and prognosis of spinal meningiomas: a Surveillance, Epidemiology, and End Results study. J Neurosurg Spine 23:3683732015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Yano SKuratsu J: Indications for surgery in patients with asymptomatic meningiomas based on an extensive experience. J Neurosurg 105:5385432006

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Article Information

Correspondence Ankit I. Mehta: University of Illinois at Chicago, Chicago, IL. ankitm@uic.edu.

INCLUDE WHEN CITING DOI: 10.3171/2019.3.FOCUS1971.

A.K.R. and J.S.R. contributed equally to this paper.

Disclosures Dr. Mehta has been a consultant for DePuy Synthes and Globus Medical.

© AANS, except where prohibited by US copyright law.

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    Kaplan-Meier survival curve assessing cause-specific mortality for patients with atypical meningiomas. No statistically significant differences were noted between treatment groups.

References

  • 1

    Agarwal VMcCutcheon BAHughes JDCarlson MLGlasgow AEHabermann EB: Trends in management of intracranial meningiomas: analysis of 49,921 cases from modern cohort. World Neurosurg 106:1451512017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Aizer AABi WLKandola MSLee EQNayak LRinne ML: Extent of resection and overall survival for patients with atypical and malignant meningioma. Cancer 121:437643812015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Barthélemy ELoewenstern JKonuthula NPain MHall JGovindaraj S: Primary management of atypical meningioma: treatment patterns and survival outcomes by patient age. J Cancer Res Clin Oncol 144:9699782018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Buerki RAHorbinski CMKruser THorowitz PMJames CDLukas RV: An overview of meningiomas. Future Oncol 14:216121772018

  • 5

    Cahill KSClaus EB: Treatment and survival of patients with nonmalignant intracranial meningioma: results from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Clinical article. J Neurosurg 115:2592672011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Champeaux CHouston DDunn L: Atypical meningioma. A study on recurrence and disease-specific survival. Neurochirurgie 63:2732812017

  • 7

    Chan AWBernstein KDAdams JAParambi RJLoeffler JS: Dose escalation with proton radiation therapy for high-grade meningiomas. Technol Cancer Res Treat 11:6076142012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Dudley RWRTorok MRRandall SBéland BHandler MHMulcahy-Levy JM: Pediatric versus adult meningioma: comparison of epidemiology, treatments, and outcomes using the Surveillance, Epidemiology, and End Results database. J Neurooncol 137:6216292018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Dziuk TWWoo SButler EBThornby JGrossman RDennis WS: Malignant meningioma: an indication for initial aggressive surgery and adjuvant radiotherapy. J Neurooncol 37:1771881998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Garzon-Muvdi TYang WLim MBrem HHuang J: Atypical and anaplastic meningioma: outcomes in a population based study. J Neurooncol 133:3213302017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Grossbach AJMahaney KBMenezes AH: Pediatric meningiomas: 65-year experience at a single institution. J Neurosurg Pediatr 20:42502017

  • 12

    Heinze G: A comparative investigation of methods for logistic regression with separated or nearly separated data. Stat Med 25:421642262006

  • 13

    Karhade AVLarsen AMGCote DJDubois HMSmith TR: National databases for neurosurgical outcomes research: options, strengths, and limitations. Neurosurgery 83:3333442018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Kotecha RSJunckerstorff RCLee SCole CHGottardo NG: Pediatric meningioma: current approaches and future direction. J Neurooncol 104:1102011

  • 15

    Ostrom QTGittleman HFulop JLiu MBlanda RKromer C: CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol 17 (Suppl 4):iv1iv622015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Paldor IAwad MSufaro YZKaye AHShoshan Y: Review of controversies in management of non-benign meningioma. J Clin Neurosci 31:37462016

  • 17

    Rogers LBarani IChamberlain MKaley TJMcDermott MRaizer J: Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J Neurosurg 122:4232015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Solheim OTorsteinsen MJohannesen TBJakola AS: Effects of cerebral magnetic resonance imaging in outpatients on observed incidence of intracranial tumors and patient survival: a national observational study. J Neurosurg 120:8278322014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Stessin AMSchwartz AJudanin GPannullo SCBoockvar JASchwartz TH: Does adjuvant external-beam radiotherapy improve outcomes for nonbenign meningiomas? A Surveillance, Epidemiology, and End Results (SEER)–based analysis. J Neurosurg 117:6696752012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Sughrue MESanai NShangari GParsa ATBerger MSMcDermott MW: Outcome and survival following primary and repeat surgery for World Health Organization Grade III meningiomas. J Neurosurg 113:2022092010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Vernooij MWIkram MATanghe HLVincent AJHofman AKrestin GP: Incidental findings on brain MRI in the general population. N Engl J Med 357:182118282007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    von Elm EAltman DGEgger MPocock SJGøtzsche PCVandenbroucke JP: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61:3443492008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Westwick HJShamji MF: Effects of sex on the incidence and prognosis of spinal meningiomas: a Surveillance, Epidemiology, and End Results study. J Neurosurg Spine 23:3683732015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Yano SKuratsu J: Indications for surgery in patients with asymptomatic meningiomas based on an extensive experience. J Neurosurg 105:5385432006

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